Bipolar Disorder

Discuss this article at www.facebook.com/CurrentPsychiatry

Mr. Z, age 61, is referred by his primary care clinician to the hospital’s medical service with increasing depressive symptoms and non-pruritic rash. He has a history of bipolar I disorder for >30 years. When the primary care physician evaluated Mr. Z, his vitals were normal, but blood work revealed mild anemia and thrombocytopenia of 34 x10³/μL, which prompted referral to the hospital. During admission, the psychiatric consultation service is called to evaluate Mr. Z’s depressive symptoms.

Mr. Z reports having chronic sleep problems and feeling cold and tired, shivering at times, but has no pain. He says he’s worried because he feels severely depressed, worthless, and hopeless, but denies suicidal ideation and psychosis. Mr. Z says he started experiencing increasingly depressed mood, anhedonia, insomnia, fatigue, poor appetite, and concentration 2 months ago. At that time his outpatient psychiatrist started Mr. Z on risperidone, 6 mg/d, and divalproex, 1,500 mg at bedtime because of emerging mood symptoms, after he was off medication for 7 months. Mr. Z attributed his worsened mood symptoms to being overwhelmed by several psychosocial stressors, including going through a complicated divorce, financial problems, and homelessness after being evicted from his apartment.

A review of Mr. Z’s psychiatric history reveals several remote hospitalizations—the last was 7 years ago—for escalated manic symptoms after he stopped taking his medication. He denies past suicide attempts. Mr. Z says he is compliant with his current medication regimen—risperidone, 6 mg/d, and divalproex, 1,500 mg at bedtime. He denies illicit drug use and says he drinks “a couple of beers, mostly on weekends.” Family history is positive for depression and bipolar II disorder.

His medical history is significant for hypothyroidism after goiter removal 6 years ago, for which he takes levothyroxine, 150 mcg/d, and a sports injury-related splenectomy in childhood. He reports no allergies. Vital signs at the time of admission are temperature, 99.1°F; pulse, 98 beats per minute; respiration, 16 breaths per minute; blood pressure, 123/73 mm/Hg; and oxygen saturation, 97%.

During the interview, Mr. Z presents with tired facies and exhibits psychomotor retardation. He has to force himself to stay engaged in the evaluation and maintain eye contact. His speech is clear, regular, and soft. Mr. Z says he is “very depressed”; his affect is constricted, almost flat, stable, and consistent with depressed mood. His thought process is linear and somewhat concrete and his thought content is notable for hopelessness, although Mr. Z continues to deny suicidal or homicidal ideations. No hallucinations or apparent delusions are noted. Insight and judgment are fair. Mr. Z understands his current mental state; however, he displays some lack of knowledge regarding his current hospitalization. Cognition is intact.

The authors’ observations

The differential diagnosis in patients presenting with mood changes is extensive (Table 1)¹ and in Mr. Z’s case includes several precipitating and perpetuating factors. Mr. Z presents with severe depressive symptoms and meets DSM-IV-TR criteria for a major depressive episode (MDE). This presentation is not typical of his bipolar I disorder because Mr. Z has never experienced an MDE and usually presents with escalating hypomanic/manic symptoms in the context of medication nonadherence. Nevertheless, Mr. Z has several risk factors for severe depression, including a family psychiatric history, multiple enduring social stressors and life crises, and medical conditions.

In the general population, the lifetime risk for developing depression is 8% to 17%.² The risk of developing a mood disorder increases significantly if a first-degree relative is diagnosed with a mood disorder; the relative risk is 10.3 for bipolar disorder and 3.2 for depression.³ Additionally, Mr. Z is going through a complicated divorce, has financial problems, and is homeless, all of which could trigger an MDE. Furthermore, hypothyroidism shares many symptoms of depression, including fatigue, lethargy, anhedonia, cold intolerance, and low mood; mental status changes frequently are the initial presentation of thyroid problems.⁴ Physicians started Mr. Z on a new medication regimen (risperidone and divalproex) to control mood instability, which coincided with symptom onset. Atypical antipsychotics have been reported to precipitate depressive symptoms; their side effect profile includes extrapyramidal effects, such as flat affect, which can be mistaken for depression.⁵ Rapid valproate titration can mimic neurovegetative symptoms of depression and cause dose-dependent thrombocytopenia and rash, which could explain his initial presentation.⁶ Finally, Mr. Z’s history of traumatic splenectomy, change in mental status, and thrombocytopenia suggest an infectious etiology.

Table 1

Differential diagnosis in patients presenting with mood changes

Possible infectious causes

The increased prevalence of immune suppression due to human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) or from therapeutic modalities such as cancer therapy or splenectomy has led to an increased number of chronic CNS infections, manifesting with an array of neuropsychiatric symptoms and nonspecific physiological reactions.^1,7 Mr. Z complains of a 2-month period of worsening depression that could suggest an infectious process with an insidious onset. Some infectious agents that can cause chronic CNS infection and encephalopathy are presented in Table 2.⁸ HIV, tuberculosis, syphilis, Lyme disease, and herpes simplex virus are becoming more prevalent and can present with neuropsychiatric symptoms.¹ For example, in addition to thrombocytopenia and low-grade fever, patients with HIV may exhibit a broad range of neuropsychiatric symptoms such as cognitive problems, impaired executive and motor functioning, sleep disturbance, and anxiety. These patients frequently present with low mood and neurovegetative symptoms of depression.⁷ Similarly, the same tick responsible for Lyme disease infection can transmit other infectious agents that can cause thrombocytopenia, including Babesia, Ehrlichia chaffeensis, Anaplasma phagocytophilum, and human Ewingii ehrlichiosis.

The authors’ observations

Diagnosis of a mood change, particularly an MDE, is clinical, based on careful psychiatric evaluation using standardized criteria rather than a specific lab test. However, some laboratory studies (Table 3)¹ are useful in differentiating medical illnesses that may present with depression. Mr. Z’s presentation warrants investigating these tests. His history of traumatic splenectomy and night sweats suggests an infection. The team’s initial recommendations include laboratory tests, discontinuing divalproex because it may be causing thrombocytopenia, and decreasing risperidone to 2 mg/d to improve his fatigue and possibly developed extrapyramidal symptoms.

Table 2

Potential infectious causes of chronic encephalopathy

Table 3

Differentiating medical illnesses that may mimic depression

TREATMENT: Cause revealed

Mr. Z develops a persistent fever of 102°F with continuous profuse sweating and a hypotensive episode. Blood work reveals mild anemia, thrombocytopenia, and increased coagulation parameters with high D-dimer and low fibrinogen, consistent with diagnosis of disseminated intravascular coagulation (DIC) secondary to infectious etiology. Thyroid and HIV tests are negative. After further evaluation, Mr. Z remembers that 4 months earlier he removed several ticks from his legs after hunting; he also remembers experiencing shivering and night sweats several weeks before he was hospitalized. His blood smear is positive for babesiosis and further testing confirms positive Lyme antibodies. Mr. Z is started on aggressive hemodynamic stabilization and a pathogen-tailored course of antibiotics for several weeks. This results in improvement and discharge home in a stable condition. His depression and fatigue improve but do not fully remit by the time he is discharged.

The authors’ observations

Lyme disease is one of the fastest-growing infectious diseases in the United States.⁹ The prevalence of positive Lyme antibodies is 30% higher in psychiatric populations than the general population.¹⁰ Lyme disease is transmitted by deer tick bite, often undetected, that is infected with spirochete Borrelia burgdorferi. To be infectious, ticks need to be attached to the skin for 24 to 48 hours,^11,12 although individual cases have reported transmission in <24 hours. The clinical manifestations of Lyme disease can be divided into 3 phases:

• early localized phase, characterized by the distinctive skin lesion erythema migrans with or without constitutional symptoms
• early disseminated phase, characterized by multiple erythema migrans lesions and neurologic and/or cardiac findings
• late or chronic disease associated with intermittent/persistent arthritis and/or neurologic problems.^11,13

The clinical features of each stage frequently overlap and some patients in a later stage of Lyme disease do not have prior signs or symptoms of the disease. Because it is a multisystem disease, Lyme disease can attack the CNS in the form of neuroborreliosis, a clinical diagnosis, without involving other systems, and its neuropsychiatric manifestations can resemble neurosyphilis because both organisms are spirochetes.^11,13,14 CNS disorders have been found in up to 40% of Lyme disease cases.¹¹ In neuroborreliosis, cognitive problems usually predominate; however, neuroborreliosis can mimic multiple brain diseases presenting with various neurologic and psychiatric symptoms (Table 4)^14,15 and can present at any time after the tick bite. Furthermore neuroborreliosis is difficult to diagnose because symptoms may remain dormant and emerge after several years.^11,13,14Borrelia burgdorferi is challenging to isolate and grow in the lab, and enzyme-linked immunosorbent assay (ELISA) testing for antibodies is highly specific but not very sensitive,¹⁶ frequently giving false negative results. Western blot confirms the diagnosis.

Table 4

Late-stage neuropsychiatric symptoms of Lyme disease

Mr. Z’s presentation also reflects co-infection with babesiosis. Babesia is malaria-like protozoa diagnosed by blood smear that can cause a fatal illness in immuno-compromised patients. The clinical picture varies from mild symptoms such as night sweats, chills, arthralgias, and anorexia with thrombocytopenia to severe and potentially fatal outcomes in immunocompromised patients, including DIC, acute renal failure, sepsis, congestive heart failure, and myocardial infarction.¹¹ Risk factors for the severest forms of babesiosis are age >50, co-infection with Lyme disease, and splenectomy,¹¹ all of which were present in Mr. Z. Co-infected patients experience fatigue, headache, anorexia, and emotional lability more frequently than those with Lyme disease alone.¹²

Treatment options

Treatment of Lyme disease/neuroborreliosis is complex. The mainstay approach is antibiotics. Despite adequate treatment, many patients experience continued impairment, including chronic pain, fatigue, and cognitive and psychiatric symptoms.^11,14 There is some evidence Borrelia burgdorferi can persist and re-emerge after adequate treatment.^14,17 The National Institute of Health sponsored several clinical trials of prolonged antibiotic treatment for chronic Lyme disease. Some results suggested improvement in fatigue and cognitive function, although these results were not sustained.¹⁸

There is a strong link between mental illness and increased prevalence of positive Lyme disease antibodies.¹⁰ Several studies report increased risk of infection during psychological stress that may be related to an altered immune system response.¹⁹ Evidence suggests that Borrelia burgdorferi can alter immune system response, making T cells more reactive not only to Borrelia burgdorferi antigens but also to host antigens,²⁰ creating autoimmune inflammatory reactions that could explain chronic neuropsychiatric symptoms. It appears Lyme disease antigens can mimic certain autoantigens (for example, in the thyroid gland).²¹ Whether there is a role for autoimmune therapy in treating chronic symptoms needs to be investigated.

Once Lyme disease is diagnosed, educating patients and families becomes an important part of treatment because many patients report feeling stigmatized by the diagnosis. Referral to a Lyme disease support group may be beneficial. Patients with neuropsychiatric symptoms that persist after antibiotic treatment should be offered symptom-based treatment, including medications and therapy.

Related Resource

• Centers for Disease Control and Prevention. Lyme disease: Resources for clinicians. www.cdc.gov/lyme/healthcare/clinicians.html.

Drug Brand Names

• Divalproex sodium • Depakote
• Levothyroxine • Levoxyl, Synthroid
• Risperidone • Risperdal

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Mr. Z, age 61, is referred by his primary care clinician to the hospital’s medical service with increasing depressive symptoms and non-pruritic rash. He has a history of bipolar I disorder for >30 years. When the primary care physician evaluated Mr. Z, his vitals were normal, but blood work revealed mild anemia and thrombocytopenia of 34 x10³/μL, which prompted referral to the hospital. During admission, the psychiatric consultation service is called to evaluate Mr. Z’s depressive symptoms.

Mr. Z reports having chronic sleep problems and feeling cold and tired, shivering at times, but has no pain. He says he’s worried because he feels severely depressed, worthless, and hopeless, but denies suicidal ideation and psychosis. Mr. Z says he started experiencing increasingly depressed mood, anhedonia, insomnia, fatigue, poor appetite, and concentration 2 months ago. At that time his outpatient psychiatrist started Mr. Z on risperidone, 6 mg/d, and divalproex, 1,500 mg at bedtime because of emerging mood symptoms, after he was off medication for 7 months. Mr. Z attributed his worsened mood symptoms to being overwhelmed by several psychosocial stressors, including going through a complicated divorce, financial problems, and homelessness after being evicted from his apartment.

A review of Mr. Z’s psychiatric history reveals several remote hospitalizations—the last was 7 years ago—for escalated manic symptoms after he stopped taking his medication. He denies past suicide attempts. Mr. Z says he is compliant with his current medication regimen—risperidone, 6 mg/d, and divalproex, 1,500 mg at bedtime. He denies illicit drug use and says he drinks “a couple of beers, mostly on weekends.” Family history is positive for depression and bipolar II disorder.

His medical history is significant for hypothyroidism after goiter removal 6 years ago, for which he takes levothyroxine, 150 mcg/d, and a sports injury-related splenectomy in childhood. He reports no allergies. Vital signs at the time of admission are temperature, 99.1°F; pulse, 98 beats per minute; respiration, 16 breaths per minute; blood pressure, 123/73 mm/Hg; and oxygen saturation, 97%.

During the interview, Mr. Z presents with tired facies and exhibits psychomotor retardation. He has to force himself to stay engaged in the evaluation and maintain eye contact. His speech is clear, regular, and soft. Mr. Z says he is “very depressed”; his affect is constricted, almost flat, stable, and consistent with depressed mood. His thought process is linear and somewhat concrete and his thought content is notable for hopelessness, although Mr. Z continues to deny suicidal or homicidal ideations. No hallucinations or apparent delusions are noted. Insight and judgment are fair. Mr. Z understands his current mental state; however, he displays some lack of knowledge regarding his current hospitalization. Cognition is intact.

The authors’ observations

The differential diagnosis in patients presenting with mood changes is extensive (Table 1)¹ and in Mr. Z’s case includes several precipitating and perpetuating factors. Mr. Z presents with severe depressive symptoms and meets DSM-IV-TR criteria for a major depressive episode (MDE). This presentation is not typical of his bipolar I disorder because Mr. Z has never experienced an MDE and usually presents with escalating hypomanic/manic symptoms in the context of medication nonadherence. Nevertheless, Mr. Z has several risk factors for severe depression, including a family psychiatric history, multiple enduring social stressors and life crises, and medical conditions.

In the general population, the lifetime risk for developing depression is 8% to 17%.² The risk of developing a mood disorder increases significantly if a first-degree relative is diagnosed with a mood disorder; the relative risk is 10.3 for bipolar disorder and 3.2 for depression.³ Additionally, Mr. Z is going through a complicated divorce, has financial problems, and is homeless, all of which could trigger an MDE. Furthermore, hypothyroidism shares many symptoms of depression, including fatigue, lethargy, anhedonia, cold intolerance, and low mood; mental status changes frequently are the initial presentation of thyroid problems.⁴ Physicians started Mr. Z on a new medication regimen (risperidone and divalproex) to control mood instability, which coincided with symptom onset. Atypical antipsychotics have been reported to precipitate depressive symptoms; their side effect profile includes extrapyramidal effects, such as flat affect, which can be mistaken for depression.⁵ Rapid valproate titration can mimic neurovegetative symptoms of depression and cause dose-dependent thrombocytopenia and rash, which could explain his initial presentation.⁶ Finally, Mr. Z’s history of traumatic splenectomy, change in mental status, and thrombocytopenia suggest an infectious etiology.

Table 1

Differential diagnosis in patients presenting with mood changes

Possible infectious causes

The increased prevalence of immune suppression due to human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) or from therapeutic modalities such as cancer therapy or splenectomy has led to an increased number of chronic CNS infections, manifesting with an array of neuropsychiatric symptoms and nonspecific physiological reactions.^1,7 Mr. Z complains of a 2-month period of worsening depression that could suggest an infectious process with an insidious onset. Some infectious agents that can cause chronic CNS infection and encephalopathy are presented in Table 2.⁸ HIV, tuberculosis, syphilis, Lyme disease, and herpes simplex virus are becoming more prevalent and can present with neuropsychiatric symptoms.¹ For example, in addition to thrombocytopenia and low-grade fever, patients with HIV may exhibit a broad range of neuropsychiatric symptoms such as cognitive problems, impaired executive and motor functioning, sleep disturbance, and anxiety. These patients frequently present with low mood and neurovegetative symptoms of depression.⁷ Similarly, the same tick responsible for Lyme disease infection can transmit other infectious agents that can cause thrombocytopenia, including Babesia, Ehrlichia chaffeensis, Anaplasma phagocytophilum, and human Ewingii ehrlichiosis.

The authors’ observations

Diagnosis of a mood change, particularly an MDE, is clinical, based on careful psychiatric evaluation using standardized criteria rather than a specific lab test. However, some laboratory studies (Table 3)¹ are useful in differentiating medical illnesses that may present with depression. Mr. Z’s presentation warrants investigating these tests. His history of traumatic splenectomy and night sweats suggests an infection. The team’s initial recommendations include laboratory tests, discontinuing divalproex because it may be causing thrombocytopenia, and decreasing risperidone to 2 mg/d to improve his fatigue and possibly developed extrapyramidal symptoms.

Table 2

Potential infectious causes of chronic encephalopathy

Table 3

Differentiating medical illnesses that may mimic depression

TREATMENT: Cause revealed

Mr. Z develops a persistent fever of 102°F with continuous profuse sweating and a hypotensive episode. Blood work reveals mild anemia, thrombocytopenia, and increased coagulation parameters with high D-dimer and low fibrinogen, consistent with diagnosis of disseminated intravascular coagulation (DIC) secondary to infectious etiology. Thyroid and HIV tests are negative. After further evaluation, Mr. Z remembers that 4 months earlier he removed several ticks from his legs after hunting; he also remembers experiencing shivering and night sweats several weeks before he was hospitalized. His blood smear is positive for babesiosis and further testing confirms positive Lyme antibodies. Mr. Z is started on aggressive hemodynamic stabilization and a pathogen-tailored course of antibiotics for several weeks. This results in improvement and discharge home in a stable condition. His depression and fatigue improve but do not fully remit by the time he is discharged.

The authors’ observations

Lyme disease is one of the fastest-growing infectious diseases in the United States.⁹ The prevalence of positive Lyme antibodies is 30% higher in psychiatric populations than the general population.¹⁰ Lyme disease is transmitted by deer tick bite, often undetected, that is infected with spirochete Borrelia burgdorferi. To be infectious, ticks need to be attached to the skin for 24 to 48 hours,^11,12 although individual cases have reported transmission in <24 hours. The clinical manifestations of Lyme disease can be divided into 3 phases:

• early localized phase, characterized by the distinctive skin lesion erythema migrans with or without constitutional symptoms
• early disseminated phase, characterized by multiple erythema migrans lesions and neurologic and/or cardiac findings
• late or chronic disease associated with intermittent/persistent arthritis and/or neurologic problems.^11,13

The clinical features of each stage frequently overlap and some patients in a later stage of Lyme disease do not have prior signs or symptoms of the disease. Because it is a multisystem disease, Lyme disease can attack the CNS in the form of neuroborreliosis, a clinical diagnosis, without involving other systems, and its neuropsychiatric manifestations can resemble neurosyphilis because both organisms are spirochetes.^11,13,14 CNS disorders have been found in up to 40% of Lyme disease cases.¹¹ In neuroborreliosis, cognitive problems usually predominate; however, neuroborreliosis can mimic multiple brain diseases presenting with various neurologic and psychiatric symptoms (Table 4)^14,15 and can present at any time after the tick bite. Furthermore neuroborreliosis is difficult to diagnose because symptoms may remain dormant and emerge after several years.^11,13,14Borrelia burgdorferi is challenging to isolate and grow in the lab, and enzyme-linked immunosorbent assay (ELISA) testing for antibodies is highly specific but not very sensitive,¹⁶ frequently giving false negative results. Western blot confirms the diagnosis.

Table 4

Late-stage neuropsychiatric symptoms of Lyme disease

Mr. Z’s presentation also reflects co-infection with babesiosis. Babesia is malaria-like protozoa diagnosed by blood smear that can cause a fatal illness in immuno-compromised patients. The clinical picture varies from mild symptoms such as night sweats, chills, arthralgias, and anorexia with thrombocytopenia to severe and potentially fatal outcomes in immunocompromised patients, including DIC, acute renal failure, sepsis, congestive heart failure, and myocardial infarction.¹¹ Risk factors for the severest forms of babesiosis are age >50, co-infection with Lyme disease, and splenectomy,¹¹ all of which were present in Mr. Z. Co-infected patients experience fatigue, headache, anorexia, and emotional lability more frequently than those with Lyme disease alone.¹²

Treatment options

Treatment of Lyme disease/neuroborreliosis is complex. The mainstay approach is antibiotics. Despite adequate treatment, many patients experience continued impairment, including chronic pain, fatigue, and cognitive and psychiatric symptoms.^11,14 There is some evidence Borrelia burgdorferi can persist and re-emerge after adequate treatment.^14,17 The National Institute of Health sponsored several clinical trials of prolonged antibiotic treatment for chronic Lyme disease. Some results suggested improvement in fatigue and cognitive function, although these results were not sustained.¹⁸

There is a strong link between mental illness and increased prevalence of positive Lyme disease antibodies.¹⁰ Several studies report increased risk of infection during psychological stress that may be related to an altered immune system response.¹⁹ Evidence suggests that Borrelia burgdorferi can alter immune system response, making T cells more reactive not only to Borrelia burgdorferi antigens but also to host antigens,²⁰ creating autoimmune inflammatory reactions that could explain chronic neuropsychiatric symptoms. It appears Lyme disease antigens can mimic certain autoantigens (for example, in the thyroid gland).²¹ Whether there is a role for autoimmune therapy in treating chronic symptoms needs to be investigated.

Once Lyme disease is diagnosed, educating patients and families becomes an important part of treatment because many patients report feeling stigmatized by the diagnosis. Referral to a Lyme disease support group may be beneficial. Patients with neuropsychiatric symptoms that persist after antibiotic treatment should be offered symptom-based treatment, including medications and therapy.

Related Resource

• Centers for Disease Control and Prevention. Lyme disease: Resources for clinicians. www.cdc.gov/lyme/healthcare/clinicians.html.

Drug Brand Names

• Divalproex sodium • Depakote
• Levothyroxine • Levoxyl, Synthroid
• Risperidone • Risperdal

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Mr. Z, age 61, is referred by his primary care clinician to the hospital’s medical service with increasing depressive symptoms and non-pruritic rash. He has a history of bipolar I disorder for >30 years. When the primary care physician evaluated Mr. Z, his vitals were normal, but blood work revealed mild anemia and thrombocytopenia of 34 x10³/μL, which prompted referral to the hospital. During admission, the psychiatric consultation service is called to evaluate Mr. Z’s depressive symptoms.

Mr. Z reports having chronic sleep problems and feeling cold and tired, shivering at times, but has no pain. He says he’s worried because he feels severely depressed, worthless, and hopeless, but denies suicidal ideation and psychosis. Mr. Z says he started experiencing increasingly depressed mood, anhedonia, insomnia, fatigue, poor appetite, and concentration 2 months ago. At that time his outpatient psychiatrist started Mr. Z on risperidone, 6 mg/d, and divalproex, 1,500 mg at bedtime because of emerging mood symptoms, after he was off medication for 7 months. Mr. Z attributed his worsened mood symptoms to being overwhelmed by several psychosocial stressors, including going through a complicated divorce, financial problems, and homelessness after being evicted from his apartment.

A review of Mr. Z’s psychiatric history reveals several remote hospitalizations—the last was 7 years ago—for escalated manic symptoms after he stopped taking his medication. He denies past suicide attempts. Mr. Z says he is compliant with his current medication regimen—risperidone, 6 mg/d, and divalproex, 1,500 mg at bedtime. He denies illicit drug use and says he drinks “a couple of beers, mostly on weekends.” Family history is positive for depression and bipolar II disorder.

His medical history is significant for hypothyroidism after goiter removal 6 years ago, for which he takes levothyroxine, 150 mcg/d, and a sports injury-related splenectomy in childhood. He reports no allergies. Vital signs at the time of admission are temperature, 99.1°F; pulse, 98 beats per minute; respiration, 16 breaths per minute; blood pressure, 123/73 mm/Hg; and oxygen saturation, 97%.

During the interview, Mr. Z presents with tired facies and exhibits psychomotor retardation. He has to force himself to stay engaged in the evaluation and maintain eye contact. His speech is clear, regular, and soft. Mr. Z says he is “very depressed”; his affect is constricted, almost flat, stable, and consistent with depressed mood. His thought process is linear and somewhat concrete and his thought content is notable for hopelessness, although Mr. Z continues to deny suicidal or homicidal ideations. No hallucinations or apparent delusions are noted. Insight and judgment are fair. Mr. Z understands his current mental state; however, he displays some lack of knowledge regarding his current hospitalization. Cognition is intact.

The authors’ observations

The differential diagnosis in patients presenting with mood changes is extensive (Table 1)¹ and in Mr. Z’s case includes several precipitating and perpetuating factors. Mr. Z presents with severe depressive symptoms and meets DSM-IV-TR criteria for a major depressive episode (MDE). This presentation is not typical of his bipolar I disorder because Mr. Z has never experienced an MDE and usually presents with escalating hypomanic/manic symptoms in the context of medication nonadherence. Nevertheless, Mr. Z has several risk factors for severe depression, including a family psychiatric history, multiple enduring social stressors and life crises, and medical conditions.

In the general population, the lifetime risk for developing depression is 8% to 17%.² The risk of developing a mood disorder increases significantly if a first-degree relative is diagnosed with a mood disorder; the relative risk is 10.3 for bipolar disorder and 3.2 for depression.³ Additionally, Mr. Z is going through a complicated divorce, has financial problems, and is homeless, all of which could trigger an MDE. Furthermore, hypothyroidism shares many symptoms of depression, including fatigue, lethargy, anhedonia, cold intolerance, and low mood; mental status changes frequently are the initial presentation of thyroid problems.⁴ Physicians started Mr. Z on a new medication regimen (risperidone and divalproex) to control mood instability, which coincided with symptom onset. Atypical antipsychotics have been reported to precipitate depressive symptoms; their side effect profile includes extrapyramidal effects, such as flat affect, which can be mistaken for depression.⁵ Rapid valproate titration can mimic neurovegetative symptoms of depression and cause dose-dependent thrombocytopenia and rash, which could explain his initial presentation.⁶ Finally, Mr. Z’s history of traumatic splenectomy, change in mental status, and thrombocytopenia suggest an infectious etiology.

Table 1

Differential diagnosis in patients presenting with mood changes

Possible infectious causes

The increased prevalence of immune suppression due to human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) or from therapeutic modalities such as cancer therapy or splenectomy has led to an increased number of chronic CNS infections, manifesting with an array of neuropsychiatric symptoms and nonspecific physiological reactions.^1,7 Mr. Z complains of a 2-month period of worsening depression that could suggest an infectious process with an insidious onset. Some infectious agents that can cause chronic CNS infection and encephalopathy are presented in Table 2.⁸ HIV, tuberculosis, syphilis, Lyme disease, and herpes simplex virus are becoming more prevalent and can present with neuropsychiatric symptoms.¹ For example, in addition to thrombocytopenia and low-grade fever, patients with HIV may exhibit a broad range of neuropsychiatric symptoms such as cognitive problems, impaired executive and motor functioning, sleep disturbance, and anxiety. These patients frequently present with low mood and neurovegetative symptoms of depression.⁷ Similarly, the same tick responsible for Lyme disease infection can transmit other infectious agents that can cause thrombocytopenia, including Babesia, Ehrlichia chaffeensis, Anaplasma phagocytophilum, and human Ewingii ehrlichiosis.

The authors’ observations

Diagnosis of a mood change, particularly an MDE, is clinical, based on careful psychiatric evaluation using standardized criteria rather than a specific lab test. However, some laboratory studies (Table 3)¹ are useful in differentiating medical illnesses that may present with depression. Mr. Z’s presentation warrants investigating these tests. His history of traumatic splenectomy and night sweats suggests an infection. The team’s initial recommendations include laboratory tests, discontinuing divalproex because it may be causing thrombocytopenia, and decreasing risperidone to 2 mg/d to improve his fatigue and possibly developed extrapyramidal symptoms.

Table 2

Potential infectious causes of chronic encephalopathy

Table 3

Differentiating medical illnesses that may mimic depression

TREATMENT: Cause revealed

Mr. Z develops a persistent fever of 102°F with continuous profuse sweating and a hypotensive episode. Blood work reveals mild anemia, thrombocytopenia, and increased coagulation parameters with high D-dimer and low fibrinogen, consistent with diagnosis of disseminated intravascular coagulation (DIC) secondary to infectious etiology. Thyroid and HIV tests are negative. After further evaluation, Mr. Z remembers that 4 months earlier he removed several ticks from his legs after hunting; he also remembers experiencing shivering and night sweats several weeks before he was hospitalized. His blood smear is positive for babesiosis and further testing confirms positive Lyme antibodies. Mr. Z is started on aggressive hemodynamic stabilization and a pathogen-tailored course of antibiotics for several weeks. This results in improvement and discharge home in a stable condition. His depression and fatigue improve but do not fully remit by the time he is discharged.

The authors’ observations

Lyme disease is one of the fastest-growing infectious diseases in the United States.⁹ The prevalence of positive Lyme antibodies is 30% higher in psychiatric populations than the general population.¹⁰ Lyme disease is transmitted by deer tick bite, often undetected, that is infected with spirochete Borrelia burgdorferi. To be infectious, ticks need to be attached to the skin for 24 to 48 hours,^11,12 although individual cases have reported transmission in <24 hours. The clinical manifestations of Lyme disease can be divided into 3 phases:

• early localized phase, characterized by the distinctive skin lesion erythema migrans with or without constitutional symptoms
• early disseminated phase, characterized by multiple erythema migrans lesions and neurologic and/or cardiac findings
• late or chronic disease associated with intermittent/persistent arthritis and/or neurologic problems.^11,13

The clinical features of each stage frequently overlap and some patients in a later stage of Lyme disease do not have prior signs or symptoms of the disease. Because it is a multisystem disease, Lyme disease can attack the CNS in the form of neuroborreliosis, a clinical diagnosis, without involving other systems, and its neuropsychiatric manifestations can resemble neurosyphilis because both organisms are spirochetes.^11,13,14 CNS disorders have been found in up to 40% of Lyme disease cases.¹¹ In neuroborreliosis, cognitive problems usually predominate; however, neuroborreliosis can mimic multiple brain diseases presenting with various neurologic and psychiatric symptoms (Table 4)^14,15 and can present at any time after the tick bite. Furthermore neuroborreliosis is difficult to diagnose because symptoms may remain dormant and emerge after several years.^11,13,14Borrelia burgdorferi is challenging to isolate and grow in the lab, and enzyme-linked immunosorbent assay (ELISA) testing for antibodies is highly specific but not very sensitive,¹⁶ frequently giving false negative results. Western blot confirms the diagnosis.

Table 4

Late-stage neuropsychiatric symptoms of Lyme disease

Mr. Z’s presentation also reflects co-infection with babesiosis. Babesia is malaria-like protozoa diagnosed by blood smear that can cause a fatal illness in immuno-compromised patients. The clinical picture varies from mild symptoms such as night sweats, chills, arthralgias, and anorexia with thrombocytopenia to severe and potentially fatal outcomes in immunocompromised patients, including DIC, acute renal failure, sepsis, congestive heart failure, and myocardial infarction.¹¹ Risk factors for the severest forms of babesiosis are age >50, co-infection with Lyme disease, and splenectomy,¹¹ all of which were present in Mr. Z. Co-infected patients experience fatigue, headache, anorexia, and emotional lability more frequently than those with Lyme disease alone.¹²

Treatment options

Treatment of Lyme disease/neuroborreliosis is complex. The mainstay approach is antibiotics. Despite adequate treatment, many patients experience continued impairment, including chronic pain, fatigue, and cognitive and psychiatric symptoms.^11,14 There is some evidence Borrelia burgdorferi can persist and re-emerge after adequate treatment.^14,17 The National Institute of Health sponsored several clinical trials of prolonged antibiotic treatment for chronic Lyme disease. Some results suggested improvement in fatigue and cognitive function, although these results were not sustained.¹⁸

There is a strong link between mental illness and increased prevalence of positive Lyme disease antibodies.¹⁰ Several studies report increased risk of infection during psychological stress that may be related to an altered immune system response.¹⁹ Evidence suggests that Borrelia burgdorferi can alter immune system response, making T cells more reactive not only to Borrelia burgdorferi antigens but also to host antigens,²⁰ creating autoimmune inflammatory reactions that could explain chronic neuropsychiatric symptoms. It appears Lyme disease antigens can mimic certain autoantigens (for example, in the thyroid gland).²¹ Whether there is a role for autoimmune therapy in treating chronic symptoms needs to be investigated.

Once Lyme disease is diagnosed, educating patients and families becomes an important part of treatment because many patients report feeling stigmatized by the diagnosis. Referral to a Lyme disease support group may be beneficial. Patients with neuropsychiatric symptoms that persist after antibiotic treatment should be offered symptom-based treatment, including medications and therapy.

Related Resource

• Centers for Disease Control and Prevention. Lyme disease: Resources for clinicians. www.cdc.gov/lyme/healthcare/clinicians.html.

Drug Brand Names

• Divalproex sodium • Depakote
• Levothyroxine • Levoxyl, Synthroid
• Risperidone • Risperdal

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients with bipolar disorder (BD) have a high risk for suicidal ideation, suicide attempts, and suicide.^1-3 Approximately 25% to 50% of BD patients attempt suicide at least once, and their attempts often are lethal—the ratio of attempts to completed suicides in BD patients is 3:1, compared with 30:1 in the general population.⁴ Lithium has been shown to effectively stabilize BD patients’ mood and significantly reduce the rates of suicide attempts and completed suicides,^5-9 but does not reduce BD patients’ long-term suicide risk to that of the general population.

Literature on psychotherapeutic treatments for patients with BD primarily focuses on improving patients’ adherence to pharmacotherapy and achieving faster recovery and remission.¹⁰ Nonpharmacologic treatments for patients with BD include psychoeducation, family-focused psychoeducation, cognitive therapy, and interpersonal and social rhythm therapy (Table 1).¹¹ Literature on nonpharmacologic treatments to address suicidality in BD patients is limited,^12,13 and additional psychotherapeutic interventions to reduce suicide risk in BD patients are needed.¹⁴

In this article, I describe a novel psychotherapeutic intervention I use that integrates cognitive therapy principles with ideas derived from the psychosynthesis model.^15,16 It consists of teaching patients to “disidentify” from suicidal thoughts, followed by a guided-imagery exercise in which patients experience a future positive life event with all 5 senses and internalize this experience. This creates a “hook into the future” that changes the present to match the future event and acts as an antidote to suicidal thoughts. I have used this strategy successfully in many patients as an adjunct to pharmacotherapy.

Table 1

Nonpharmacologic interventions for bipolar disorder

A theoretical model

Roberto Assagioli, who established the approach to psychology called psychosynthesis, formulated a fundamental psychological principle in controlling one’s behavior: “We are dominated by everything with which our self becomes identified. We can dominate and control everything from which we disidentify ourselves.”¹⁵ According to the psychosynthesis model, it is easier to change thoughts we identify as foreign to “the self” (ego-dystonic) than thoughts we identify as being part of “the self” (ego-syntonic).

Patients whose suicidal thoughts are ego-syntonic identify with the thoughts as representing themselves and take ownership of these thoughts. Such patients are at a greater risk of acting on suicidal thoughts.

Patients whose suicidal thoughts are ego-dystonic consider the suicidal thoughts foreign to their core self and do not believe such thoughts represent them. In essence, they “disown” the thoughts and typically want to control and eliminate them. Examples of patients’ ego-syntonic vs ego-dystonic suicidal thoughts are listed in Table 2.

This construct calls for an intervention to help patients who have ego-syntonic suicidal thoughts restructure them as a manifestation of BD, rather then the patient’s core self belief. The intervention emphasizes the patient is not “a suicidal patient” but suffers from an illness that may manifest with suicidal ideation. Many BD patients overly identify with their disease, stating, “I am bipolar” or “I am suicidal.” The “I am” statement originates from the verb “to be,” which implies the disease is part of the patient’s identity. The goal of this intervention is to help the patient learn to disidentify from the disease and decide that suicidal thoughts do not represent their core self, but are a manifestation of the underlying disease.

The psychosynthesis model of helping patients disidentify and therefore disown suicidal thoughts is compatible with interventions that use mindfulness-based cognitive therapy training to teach patients to experience their thoughts as just passing through their consciousness without taking ownership of them.¹⁷

Table 2

Examples of ego-syntonic vs ego-dystonic suicidal thoughts

The intervention

Assessment of suicidality is a fundamental skill for every mental health clinician.¹⁸ The psychotherapeutic intervention I use integrates the cognitive therapy principles of reframing, relabeling, and restructuring patients’ thoughts with disidentification from dysfunctional thoughts, feelings, and desires, based on psychosynthesis principles.

First, I conduct a comprehensive mental status examination that includes an in-depth exploration of the patient’s suicidal thoughts to determine if they are ego-syntonic or ego-dystonic. I begin by asking patients to clarify and elaborate on their statements referring to suicide, asking questions such as “Is there a part of you that objects to these thoughts?” and “Is there a part of you that wants to live?” If a patient indicates that he or she does experience inner conflict regarding such thoughts, these thoughts are classified as ego-dystonic. If a patient does not have any counter thoughts regarding the suicidal thoughts and fully identifies with them, the thoughts are classified as ego-syntonic.

I follow this with a treatment plan that helps patients change their view of their suicidal thoughts. I ask the patient to change these suicidal thoughts to ego-dystonic by focusing on the following statement: “I, (patient’s name), am a human being and like all human beings, I have thoughts; however, I am not my thoughts, I am much more than that.” I ask my patient to read this out loud and to mindfully meditate on this statement several times a day to reinforce the new understanding that these suicidal thoughts are a manifestation of the chemical imbalance of the mood disorder, and do not represent the patient as a person.

This intervention is paired with a future-focused internalized imagery experience I have described in previous articles.^19,20 In this part of the treatment, the patient and I discuss a specific expected life milestone that is positive and for which he or she would want to be present (eg, children graduating from high school or college, a wedding, birth of a child/grandchild, etc.). Using guided imagery, the patient experiences this event with all 5 senses during the session. I instruct the patient to internalize the experience and bring it back from the future to the present. This creates a “hook into the future” that is coupled with this desired milestone event in the patient’s life.

The following 3 case studies provide examples of the application of this treatment intervention.

CASE 1: Disidentifying family history

Mrs. G, a 42-year-old mother of 2, suffers from bipolar II disorder with recurrent episodes of depression associated with ego-syntonic suicidal thoughts. She states that at times she feels she is a burden to her husband and children and believes they may be better off without her. She says she believes “ending it all” must be her destiny. After further investigation, I learn Mrs. G has a family history of BD and 3 relatives have committed suicide. This family history may partially explain her belief that suicide must be “in her genes.”

I discuss with Mrs. G the strategy of changing her thoughts. I tell her to write in her journal—which she brings to her sessions—the following statements: “I am a human being. I am an adult woman and mother of 2 children. I know I have thoughts but I am not my thoughts, I am much more than that. I know I have genes but I am not my genes, I am much more than that. I know I have feelings, but I am not my feelings, I am much more than that. I know I have cousins, uncles, aunts, and other relatives but I am not my relatives. I am uniquely myself, different from the others.”

I ask Mrs. G to read these statements out loud and repeat them several times a day to reinforce this new way of perceiving the suicidal thoughts and to disidentify from the thoughts and her family history as it relates to suicide.

Mrs. G and I talk about the future and expected family milestones. When I ask if her son would want her to be present at his college graduation, she says yes. We then discuss in detail the date, time of day, and location of this event, followed by a guided imagery exercise focused on the graduation. She is guided to experience this event with all 5 senses and describes the event in detail, including the expression on the faces of her husband and children, their voices, and the scent of their aftershave lotion. She hears her son saying, “Mom, I love you. Thank you for being there with me all these years. I could not have done it without you.” I ask Mrs. G to internalize these experiences and carve them into her memory. She is instructed to come back from this future-focused guided imagery experience. When her eyes open, she looks at me and describes her experience in great detail, at times using the past tense, which confirms that the future-focused event was internalized.

In her next session, Mrs. G reports an improvement in her sleep and a change in her suicidal thoughts, which now are only fleeting.

CASE 2: Experiencing graduation

Ms. J, age 17, was diagnosed with bipolar I disorder when she was 15. She has a family history of BD in her mother, 2 maternal aunts, her grandmother, and an older sister. All these women have a history of suicidal thoughts and suicide attempts requiring hospital treatment, but no completed suicides.

Ms. J has been taking an adequate combination of mood stabilizers. She has recovered from 2 previous depressive episodes and is experiencing a third relapse with suicidal thoughts. At times, she experiences these thoughts as ego-syntonic; at other times, they are ego-dystonic.

I first educate her about the nature of BD, explaining that her suicidal thoughts are a manifestation of a chemical imbalance in her brain as a result of the depressive relapse. I teach her to use guided imagery to focus on her favorite place of peace and serenity, the beach, which produces immediate relief of the intense anxiety she felt.

After we complete the disidentification exercise, I ask her to focus on her high school graduation ceremony, which is scheduled to take place in 1 year. In a state of guided imagery, she experiences her graduation from high school with all 5 senses. As she returns to a state of full alertness with her eyes open, she describes the graduation ceremony experience in detail using the past tense, as if it had already occurred, thereby creating her own hook into the future. I instruct her to write about this experience in her journal and bring it with her to the next session.

The following session, Ms. J reports that her suicide ideations have “disappeared.” She says this was accompanied by improvements in her overall mood and sleep.

CASE 3: Internalizing the future

Mr. C, a 38-year-old married father of 4 children, has bipolar II disorder and is in a depressed state. He has been treated with optimal doses of mood stabilizers and atypical antipsychotics but continues to have suicidal thoughts. These thoughts are at times ego-syntonic; he says, “My family would be better off without me.” When Mr. C’s mood improves, however, the suicidal thoughts become more ego-dystonic; he expresses fear that he might act out on the thoughts and states that he does not want to die, he really wants to live and get better. He has no history of suicide attempts.

During our session, I ask Mr. C to focus on a new perspective to understand his thoughts by repeating the following statements: “I, JC, am a human being. I know I have a bipolar mood disorder; however, I must remember I am not bipolar. I have suicidal thoughts; however, I am not my thoughts, I am much more than that. I know I want to live, to heal, and to get better. I want to be alive and well so I can see and participate in my children’s graduation from high school and be there when they get married and when my grandchildren are born.”

I teach Mr. C to use guided imagery, during which he experiences such future positive images and milestones in his life in all 5 senses and internalizes them by using the “back from the future” technique.¹⁷ By the end of the session, he reports feeling better, more hopeful, and confident in his abilities to control his suicidal thoughts. I instruct him to write in his diary about his experiences with the future-focused positive milestones and to bring this assignment to his next appointment.

At his next appointment, Mr. C reports that his suicidal thoughts have become more fleeting, lasting for 10 to 30 seconds, and then spontaneously change to focus on issues of the “here and now.” When I ask him to read what he’s written, what stands out is the use of past tense verbs to describe future-focused experiences. For me, this confirms that Mr. C has internalized the future, creating the desirable “future hook” that acts as an antidote to the suicidal thoughts.

Related Resources

• Rouget BW, Aubry JM. Efficacy of psychoeducational approaches on bipolar disorders: a review of the literature. J Affect Disord. 2007;98:11-27.
• Weinberg I, Ronningstam E, Goldblatt MJ, et al. Strategies in treatment of suicidality: identification of common and treatment-specific interventions in empirically supported treatment manuals. J Clin Psychiatry. 2010;71:699-706.

Drug Brand Name

• Lithium • Eskalith, Lithobid

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients with bipolar disorder (BD) have a high risk for suicidal ideation, suicide attempts, and suicide.^1-3 Approximately 25% to 50% of BD patients attempt suicide at least once, and their attempts often are lethal—the ratio of attempts to completed suicides in BD patients is 3:1, compared with 30:1 in the general population.⁴ Lithium has been shown to effectively stabilize BD patients’ mood and significantly reduce the rates of suicide attempts and completed suicides,^5-9 but does not reduce BD patients’ long-term suicide risk to that of the general population.

Literature on psychotherapeutic treatments for patients with BD primarily focuses on improving patients’ adherence to pharmacotherapy and achieving faster recovery and remission.¹⁰ Nonpharmacologic treatments for patients with BD include psychoeducation, family-focused psychoeducation, cognitive therapy, and interpersonal and social rhythm therapy (Table 1).¹¹ Literature on nonpharmacologic treatments to address suicidality in BD patients is limited,^12,13 and additional psychotherapeutic interventions to reduce suicide risk in BD patients are needed.¹⁴

In this article, I describe a novel psychotherapeutic intervention I use that integrates cognitive therapy principles with ideas derived from the psychosynthesis model.^15,16 It consists of teaching patients to “disidentify” from suicidal thoughts, followed by a guided-imagery exercise in which patients experience a future positive life event with all 5 senses and internalize this experience. This creates a “hook into the future” that changes the present to match the future event and acts as an antidote to suicidal thoughts. I have used this strategy successfully in many patients as an adjunct to pharmacotherapy.

Table 1

Nonpharmacologic interventions for bipolar disorder

A theoretical model

Roberto Assagioli, who established the approach to psychology called psychosynthesis, formulated a fundamental psychological principle in controlling one’s behavior: “We are dominated by everything with which our self becomes identified. We can dominate and control everything from which we disidentify ourselves.”¹⁵ According to the psychosynthesis model, it is easier to change thoughts we identify as foreign to “the self” (ego-dystonic) than thoughts we identify as being part of “the self” (ego-syntonic).

Patients whose suicidal thoughts are ego-syntonic identify with the thoughts as representing themselves and take ownership of these thoughts. Such patients are at a greater risk of acting on suicidal thoughts.

Patients whose suicidal thoughts are ego-dystonic consider the suicidal thoughts foreign to their core self and do not believe such thoughts represent them. In essence, they “disown” the thoughts and typically want to control and eliminate them. Examples of patients’ ego-syntonic vs ego-dystonic suicidal thoughts are listed in Table 2.

This construct calls for an intervention to help patients who have ego-syntonic suicidal thoughts restructure them as a manifestation of BD, rather then the patient’s core self belief. The intervention emphasizes the patient is not “a suicidal patient” but suffers from an illness that may manifest with suicidal ideation. Many BD patients overly identify with their disease, stating, “I am bipolar” or “I am suicidal.” The “I am” statement originates from the verb “to be,” which implies the disease is part of the patient’s identity. The goal of this intervention is to help the patient learn to disidentify from the disease and decide that suicidal thoughts do not represent their core self, but are a manifestation of the underlying disease.

The psychosynthesis model of helping patients disidentify and therefore disown suicidal thoughts is compatible with interventions that use mindfulness-based cognitive therapy training to teach patients to experience their thoughts as just passing through their consciousness without taking ownership of them.¹⁷

Table 2

Examples of ego-syntonic vs ego-dystonic suicidal thoughts

The intervention

Assessment of suicidality is a fundamental skill for every mental health clinician.¹⁸ The psychotherapeutic intervention I use integrates the cognitive therapy principles of reframing, relabeling, and restructuring patients’ thoughts with disidentification from dysfunctional thoughts, feelings, and desires, based on psychosynthesis principles.

First, I conduct a comprehensive mental status examination that includes an in-depth exploration of the patient’s suicidal thoughts to determine if they are ego-syntonic or ego-dystonic. I begin by asking patients to clarify and elaborate on their statements referring to suicide, asking questions such as “Is there a part of you that objects to these thoughts?” and “Is there a part of you that wants to live?” If a patient indicates that he or she does experience inner conflict regarding such thoughts, these thoughts are classified as ego-dystonic. If a patient does not have any counter thoughts regarding the suicidal thoughts and fully identifies with them, the thoughts are classified as ego-syntonic.

I follow this with a treatment plan that helps patients change their view of their suicidal thoughts. I ask the patient to change these suicidal thoughts to ego-dystonic by focusing on the following statement: “I, (patient’s name), am a human being and like all human beings, I have thoughts; however, I am not my thoughts, I am much more than that.” I ask my patient to read this out loud and to mindfully meditate on this statement several times a day to reinforce the new understanding that these suicidal thoughts are a manifestation of the chemical imbalance of the mood disorder, and do not represent the patient as a person.

This intervention is paired with a future-focused internalized imagery experience I have described in previous articles.^19,20 In this part of the treatment, the patient and I discuss a specific expected life milestone that is positive and for which he or she would want to be present (eg, children graduating from high school or college, a wedding, birth of a child/grandchild, etc.). Using guided imagery, the patient experiences this event with all 5 senses during the session. I instruct the patient to internalize the experience and bring it back from the future to the present. This creates a “hook into the future” that is coupled with this desired milestone event in the patient’s life.

The following 3 case studies provide examples of the application of this treatment intervention.

CASE 1: Disidentifying family history

Mrs. G, a 42-year-old mother of 2, suffers from bipolar II disorder with recurrent episodes of depression associated with ego-syntonic suicidal thoughts. She states that at times she feels she is a burden to her husband and children and believes they may be better off without her. She says she believes “ending it all” must be her destiny. After further investigation, I learn Mrs. G has a family history of BD and 3 relatives have committed suicide. This family history may partially explain her belief that suicide must be “in her genes.”

I discuss with Mrs. G the strategy of changing her thoughts. I tell her to write in her journal—which she brings to her sessions—the following statements: “I am a human being. I am an adult woman and mother of 2 children. I know I have thoughts but I am not my thoughts, I am much more than that. I know I have genes but I am not my genes, I am much more than that. I know I have feelings, but I am not my feelings, I am much more than that. I know I have cousins, uncles, aunts, and other relatives but I am not my relatives. I am uniquely myself, different from the others.”

I ask Mrs. G to read these statements out loud and repeat them several times a day to reinforce this new way of perceiving the suicidal thoughts and to disidentify from the thoughts and her family history as it relates to suicide.

Mrs. G and I talk about the future and expected family milestones. When I ask if her son would want her to be present at his college graduation, she says yes. We then discuss in detail the date, time of day, and location of this event, followed by a guided imagery exercise focused on the graduation. She is guided to experience this event with all 5 senses and describes the event in detail, including the expression on the faces of her husband and children, their voices, and the scent of their aftershave lotion. She hears her son saying, “Mom, I love you. Thank you for being there with me all these years. I could not have done it without you.” I ask Mrs. G to internalize these experiences and carve them into her memory. She is instructed to come back from this future-focused guided imagery experience. When her eyes open, she looks at me and describes her experience in great detail, at times using the past tense, which confirms that the future-focused event was internalized.

In her next session, Mrs. G reports an improvement in her sleep and a change in her suicidal thoughts, which now are only fleeting.

CASE 2: Experiencing graduation

Ms. J, age 17, was diagnosed with bipolar I disorder when she was 15. She has a family history of BD in her mother, 2 maternal aunts, her grandmother, and an older sister. All these women have a history of suicidal thoughts and suicide attempts requiring hospital treatment, but no completed suicides.

Ms. J has been taking an adequate combination of mood stabilizers. She has recovered from 2 previous depressive episodes and is experiencing a third relapse with suicidal thoughts. At times, she experiences these thoughts as ego-syntonic; at other times, they are ego-dystonic.

I first educate her about the nature of BD, explaining that her suicidal thoughts are a manifestation of a chemical imbalance in her brain as a result of the depressive relapse. I teach her to use guided imagery to focus on her favorite place of peace and serenity, the beach, which produces immediate relief of the intense anxiety she felt.

After we complete the disidentification exercise, I ask her to focus on her high school graduation ceremony, which is scheduled to take place in 1 year. In a state of guided imagery, she experiences her graduation from high school with all 5 senses. As she returns to a state of full alertness with her eyes open, she describes the graduation ceremony experience in detail using the past tense, as if it had already occurred, thereby creating her own hook into the future. I instruct her to write about this experience in her journal and bring it with her to the next session.

The following session, Ms. J reports that her suicide ideations have “disappeared.” She says this was accompanied by improvements in her overall mood and sleep.

CASE 3: Internalizing the future

Mr. C, a 38-year-old married father of 4 children, has bipolar II disorder and is in a depressed state. He has been treated with optimal doses of mood stabilizers and atypical antipsychotics but continues to have suicidal thoughts. These thoughts are at times ego-syntonic; he says, “My family would be better off without me.” When Mr. C’s mood improves, however, the suicidal thoughts become more ego-dystonic; he expresses fear that he might act out on the thoughts and states that he does not want to die, he really wants to live and get better. He has no history of suicide attempts.

During our session, I ask Mr. C to focus on a new perspective to understand his thoughts by repeating the following statements: “I, JC, am a human being. I know I have a bipolar mood disorder; however, I must remember I am not bipolar. I have suicidal thoughts; however, I am not my thoughts, I am much more than that. I know I want to live, to heal, and to get better. I want to be alive and well so I can see and participate in my children’s graduation from high school and be there when they get married and when my grandchildren are born.”

I teach Mr. C to use guided imagery, during which he experiences such future positive images and milestones in his life in all 5 senses and internalizes them by using the “back from the future” technique.¹⁷ By the end of the session, he reports feeling better, more hopeful, and confident in his abilities to control his suicidal thoughts. I instruct him to write in his diary about his experiences with the future-focused positive milestones and to bring this assignment to his next appointment.

At his next appointment, Mr. C reports that his suicidal thoughts have become more fleeting, lasting for 10 to 30 seconds, and then spontaneously change to focus on issues of the “here and now.” When I ask him to read what he’s written, what stands out is the use of past tense verbs to describe future-focused experiences. For me, this confirms that Mr. C has internalized the future, creating the desirable “future hook” that acts as an antidote to the suicidal thoughts.

Related Resources

• Rouget BW, Aubry JM. Efficacy of psychoeducational approaches on bipolar disorders: a review of the literature. J Affect Disord. 2007;98:11-27.
• Weinberg I, Ronningstam E, Goldblatt MJ, et al. Strategies in treatment of suicidality: identification of common and treatment-specific interventions in empirically supported treatment manuals. J Clin Psychiatry. 2010;71:699-706.

Drug Brand Name

• Lithium • Eskalith, Lithobid

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients with bipolar disorder (BD) have a high risk for suicidal ideation, suicide attempts, and suicide.^1-3 Approximately 25% to 50% of BD patients attempt suicide at least once, and their attempts often are lethal—the ratio of attempts to completed suicides in BD patients is 3:1, compared with 30:1 in the general population.⁴ Lithium has been shown to effectively stabilize BD patients’ mood and significantly reduce the rates of suicide attempts and completed suicides,^5-9 but does not reduce BD patients’ long-term suicide risk to that of the general population.

Literature on psychotherapeutic treatments for patients with BD primarily focuses on improving patients’ adherence to pharmacotherapy and achieving faster recovery and remission.¹⁰ Nonpharmacologic treatments for patients with BD include psychoeducation, family-focused psychoeducation, cognitive therapy, and interpersonal and social rhythm therapy (Table 1).¹¹ Literature on nonpharmacologic treatments to address suicidality in BD patients is limited,^12,13 and additional psychotherapeutic interventions to reduce suicide risk in BD patients are needed.¹⁴

In this article, I describe a novel psychotherapeutic intervention I use that integrates cognitive therapy principles with ideas derived from the psychosynthesis model.^15,16 It consists of teaching patients to “disidentify” from suicidal thoughts, followed by a guided-imagery exercise in which patients experience a future positive life event with all 5 senses and internalize this experience. This creates a “hook into the future” that changes the present to match the future event and acts as an antidote to suicidal thoughts. I have used this strategy successfully in many patients as an adjunct to pharmacotherapy.

Table 1

Nonpharmacologic interventions for bipolar disorder

A theoretical model

Roberto Assagioli, who established the approach to psychology called psychosynthesis, formulated a fundamental psychological principle in controlling one’s behavior: “We are dominated by everything with which our self becomes identified. We can dominate and control everything from which we disidentify ourselves.”¹⁵ According to the psychosynthesis model, it is easier to change thoughts we identify as foreign to “the self” (ego-dystonic) than thoughts we identify as being part of “the self” (ego-syntonic).

Patients whose suicidal thoughts are ego-syntonic identify with the thoughts as representing themselves and take ownership of these thoughts. Such patients are at a greater risk of acting on suicidal thoughts.

Patients whose suicidal thoughts are ego-dystonic consider the suicidal thoughts foreign to their core self and do not believe such thoughts represent them. In essence, they “disown” the thoughts and typically want to control and eliminate them. Examples of patients’ ego-syntonic vs ego-dystonic suicidal thoughts are listed in Table 2.

This construct calls for an intervention to help patients who have ego-syntonic suicidal thoughts restructure them as a manifestation of BD, rather then the patient’s core self belief. The intervention emphasizes the patient is not “a suicidal patient” but suffers from an illness that may manifest with suicidal ideation. Many BD patients overly identify with their disease, stating, “I am bipolar” or “I am suicidal.” The “I am” statement originates from the verb “to be,” which implies the disease is part of the patient’s identity. The goal of this intervention is to help the patient learn to disidentify from the disease and decide that suicidal thoughts do not represent their core self, but are a manifestation of the underlying disease.

The psychosynthesis model of helping patients disidentify and therefore disown suicidal thoughts is compatible with interventions that use mindfulness-based cognitive therapy training to teach patients to experience their thoughts as just passing through their consciousness without taking ownership of them.¹⁷

Table 2

Examples of ego-syntonic vs ego-dystonic suicidal thoughts

The intervention

Assessment of suicidality is a fundamental skill for every mental health clinician.¹⁸ The psychotherapeutic intervention I use integrates the cognitive therapy principles of reframing, relabeling, and restructuring patients’ thoughts with disidentification from dysfunctional thoughts, feelings, and desires, based on psychosynthesis principles.

First, I conduct a comprehensive mental status examination that includes an in-depth exploration of the patient’s suicidal thoughts to determine if they are ego-syntonic or ego-dystonic. I begin by asking patients to clarify and elaborate on their statements referring to suicide, asking questions such as “Is there a part of you that objects to these thoughts?” and “Is there a part of you that wants to live?” If a patient indicates that he or she does experience inner conflict regarding such thoughts, these thoughts are classified as ego-dystonic. If a patient does not have any counter thoughts regarding the suicidal thoughts and fully identifies with them, the thoughts are classified as ego-syntonic.

I follow this with a treatment plan that helps patients change their view of their suicidal thoughts. I ask the patient to change these suicidal thoughts to ego-dystonic by focusing on the following statement: “I, (patient’s name), am a human being and like all human beings, I have thoughts; however, I am not my thoughts, I am much more than that.” I ask my patient to read this out loud and to mindfully meditate on this statement several times a day to reinforce the new understanding that these suicidal thoughts are a manifestation of the chemical imbalance of the mood disorder, and do not represent the patient as a person.

This intervention is paired with a future-focused internalized imagery experience I have described in previous articles.^19,20 In this part of the treatment, the patient and I discuss a specific expected life milestone that is positive and for which he or she would want to be present (eg, children graduating from high school or college, a wedding, birth of a child/grandchild, etc.). Using guided imagery, the patient experiences this event with all 5 senses during the session. I instruct the patient to internalize the experience and bring it back from the future to the present. This creates a “hook into the future” that is coupled with this desired milestone event in the patient’s life.

The following 3 case studies provide examples of the application of this treatment intervention.

CASE 1: Disidentifying family history

Mrs. G, a 42-year-old mother of 2, suffers from bipolar II disorder with recurrent episodes of depression associated with ego-syntonic suicidal thoughts. She states that at times she feels she is a burden to her husband and children and believes they may be better off without her. She says she believes “ending it all” must be her destiny. After further investigation, I learn Mrs. G has a family history of BD and 3 relatives have committed suicide. This family history may partially explain her belief that suicide must be “in her genes.”

I discuss with Mrs. G the strategy of changing her thoughts. I tell her to write in her journal—which she brings to her sessions—the following statements: “I am a human being. I am an adult woman and mother of 2 children. I know I have thoughts but I am not my thoughts, I am much more than that. I know I have genes but I am not my genes, I am much more than that. I know I have feelings, but I am not my feelings, I am much more than that. I know I have cousins, uncles, aunts, and other relatives but I am not my relatives. I am uniquely myself, different from the others.”

I ask Mrs. G to read these statements out loud and repeat them several times a day to reinforce this new way of perceiving the suicidal thoughts and to disidentify from the thoughts and her family history as it relates to suicide.

Mrs. G and I talk about the future and expected family milestones. When I ask if her son would want her to be present at his college graduation, she says yes. We then discuss in detail the date, time of day, and location of this event, followed by a guided imagery exercise focused on the graduation. She is guided to experience this event with all 5 senses and describes the event in detail, including the expression on the faces of her husband and children, their voices, and the scent of their aftershave lotion. She hears her son saying, “Mom, I love you. Thank you for being there with me all these years. I could not have done it without you.” I ask Mrs. G to internalize these experiences and carve them into her memory. She is instructed to come back from this future-focused guided imagery experience. When her eyes open, she looks at me and describes her experience in great detail, at times using the past tense, which confirms that the future-focused event was internalized.

In her next session, Mrs. G reports an improvement in her sleep and a change in her suicidal thoughts, which now are only fleeting.

CASE 2: Experiencing graduation

Ms. J, age 17, was diagnosed with bipolar I disorder when she was 15. She has a family history of BD in her mother, 2 maternal aunts, her grandmother, and an older sister. All these women have a history of suicidal thoughts and suicide attempts requiring hospital treatment, but no completed suicides.

Ms. J has been taking an adequate combination of mood stabilizers. She has recovered from 2 previous depressive episodes and is experiencing a third relapse with suicidal thoughts. At times, she experiences these thoughts as ego-syntonic; at other times, they are ego-dystonic.

I first educate her about the nature of BD, explaining that her suicidal thoughts are a manifestation of a chemical imbalance in her brain as a result of the depressive relapse. I teach her to use guided imagery to focus on her favorite place of peace and serenity, the beach, which produces immediate relief of the intense anxiety she felt.

After we complete the disidentification exercise, I ask her to focus on her high school graduation ceremony, which is scheduled to take place in 1 year. In a state of guided imagery, she experiences her graduation from high school with all 5 senses. As she returns to a state of full alertness with her eyes open, she describes the graduation ceremony experience in detail using the past tense, as if it had already occurred, thereby creating her own hook into the future. I instruct her to write about this experience in her journal and bring it with her to the next session.

The following session, Ms. J reports that her suicide ideations have “disappeared.” She says this was accompanied by improvements in her overall mood and sleep.

CASE 3: Internalizing the future

Mr. C, a 38-year-old married father of 4 children, has bipolar II disorder and is in a depressed state. He has been treated with optimal doses of mood stabilizers and atypical antipsychotics but continues to have suicidal thoughts. These thoughts are at times ego-syntonic; he says, “My family would be better off without me.” When Mr. C’s mood improves, however, the suicidal thoughts become more ego-dystonic; he expresses fear that he might act out on the thoughts and states that he does not want to die, he really wants to live and get better. He has no history of suicide attempts.

During our session, I ask Mr. C to focus on a new perspective to understand his thoughts by repeating the following statements: “I, JC, am a human being. I know I have a bipolar mood disorder; however, I must remember I am not bipolar. I have suicidal thoughts; however, I am not my thoughts, I am much more than that. I know I want to live, to heal, and to get better. I want to be alive and well so I can see and participate in my children’s graduation from high school and be there when they get married and when my grandchildren are born.”

I teach Mr. C to use guided imagery, during which he experiences such future positive images and milestones in his life in all 5 senses and internalizes them by using the “back from the future” technique.¹⁷ By the end of the session, he reports feeling better, more hopeful, and confident in his abilities to control his suicidal thoughts. I instruct him to write in his diary about his experiences with the future-focused positive milestones and to bring this assignment to his next appointment.

At his next appointment, Mr. C reports that his suicidal thoughts have become more fleeting, lasting for 10 to 30 seconds, and then spontaneously change to focus on issues of the “here and now.” When I ask him to read what he’s written, what stands out is the use of past tense verbs to describe future-focused experiences. For me, this confirms that Mr. C has internalized the future, creating the desirable “future hook” that acts as an antidote to the suicidal thoughts.

Related Resources

• Rouget BW, Aubry JM. Efficacy of psychoeducational approaches on bipolar disorders: a review of the literature. J Affect Disord. 2007;98:11-27.
• Weinberg I, Ronningstam E, Goldblatt MJ, et al. Strategies in treatment of suicidality: identification of common and treatment-specific interventions in empirically supported treatment manuals. J Clin Psychiatry. 2010;71:699-706.

Drug Brand Name

• Lithium • Eskalith, Lithobid

Disclosure

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

Atypical antipsychotics are effective in only a few of the many off-label conditions for which they are currently used, according to a meta-analysis in the Sept. 28 issue of JAMA.

In particular, there is no good evidence to support the use of atypical antipsychotics for substance abuse disorder, eating disorders, or insomnia. And the evidence for using them for posttraumatic stress disorder and personality disorders is characterized as "mixed," said Dr. Alicia Ruelaz Maher of Rand Health, Southern California Evidence-Based Practice Center, Santa Monica, and her colleagues.

Atypical antipsychotics are approved for use in schizophrenia, bipolar disorder, and, for select agents, depression. But their use has rapidly increased in recent years, and it is estimated that their off-label use doubled between 1995 and 2008.

Dr. Maher and her colleagues reviewed 2,066 articles published through May 2011 on the off-label use of aripiprazole, asenapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. For their meta-analysis, Dr. Maher and her colleagues included 162 efficacy trials and 231 trials or large observational studies that addressed adverse events (JAMA 2011;306:1359-69).

Among their findings were the following:

• "First, aripiprazole, olanzapine, and risperidone were associated with small but statistically significant benefits for the treatment of behavioral symptoms in dementia." These drugs improved psychosis, agitation, and symptoms such as hallucinations, suspiciousness, dysphoria, anxiety, aggression, disinhibition, and apathy, though they did so only to a degree "considered to be the minimum clinically observable change."

• In three large and very recent trials not included in previous meta-analyses, quetiapine showed significant benefits for generalized anxiety disorder. However, "we classified the strength of evidence for this outcome as ‘moderate,’ based on the inconsistency of results and because all [the trials] were funded by manufacturers."

• Risperidone was associated with significant improvement in OCD. But that finding was tempered by the fact there may have been publication bias affecting the pooled results.

• "The strength of evidence has decreased from moderate to low for [use of] quetiapine in patients with OCD."

• New evidence indicates that atypical antipsychotics are ineffective for eating disorders and substance abuse disorder.

• The level of evidence is mixed regarding personality disorders, and is moderate for an association of risperidone with improving PTSD."

Dr. Maher and her colleagues cautioned that most of the studies they reviewed – for example, 27 of the 38 trials of dementia and 12 of the 14 trials of anxiety – were sponsored by drug manufacturers. And they found no studies at all on the off-label use of three newer atypical antipsychotic drugs: asenapine, iloperidone, and paliperidone.

In addition, studies published after June 1, 2011, including a large randomized, control trial of risperidone for patients with military-related PTSD and symptoms resistant to selective serotonin reuptake inhibitors, were not included in the current review.

Still, evidence found in the meta-analysis should provide guidance to clinicians who are considering off-label prescribing of atypical antipsychotics, the investigators wrote.

This study was supported by the Agency for Healthcare Research and Quality, with some support from the Department of Veterans Affairs. One of Dr. Maher’s colleagues reported ties to Eli Lilly.

Atypical antipsychotics are effective in only a few of the many off-label conditions for which they are currently used, according to a meta-analysis in the Sept. 28 issue of JAMA.

In particular, there is no good evidence to support the use of atypical antipsychotics for substance abuse disorder, eating disorders, or insomnia. And the evidence for using them for posttraumatic stress disorder and personality disorders is characterized as "mixed," said Dr. Alicia Ruelaz Maher of Rand Health, Southern California Evidence-Based Practice Center, Santa Monica, and her colleagues.

Atypical antipsychotics are approved for use in schizophrenia, bipolar disorder, and, for select agents, depression. But their use has rapidly increased in recent years, and it is estimated that their off-label use doubled between 1995 and 2008.

Dr. Maher and her colleagues reviewed 2,066 articles published through May 2011 on the off-label use of aripiprazole, asenapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. For their meta-analysis, Dr. Maher and her colleagues included 162 efficacy trials and 231 trials or large observational studies that addressed adverse events (JAMA 2011;306:1359-69).

Among their findings were the following:

• "First, aripiprazole, olanzapine, and risperidone were associated with small but statistically significant benefits for the treatment of behavioral symptoms in dementia." These drugs improved psychosis, agitation, and symptoms such as hallucinations, suspiciousness, dysphoria, anxiety, aggression, disinhibition, and apathy, though they did so only to a degree "considered to be the minimum clinically observable change."

• In three large and very recent trials not included in previous meta-analyses, quetiapine showed significant benefits for generalized anxiety disorder. However, "we classified the strength of evidence for this outcome as ‘moderate,’ based on the inconsistency of results and because all [the trials] were funded by manufacturers."

• Risperidone was associated with significant improvement in OCD. But that finding was tempered by the fact there may have been publication bias affecting the pooled results.

• "The strength of evidence has decreased from moderate to low for [use of] quetiapine in patients with OCD."

• New evidence indicates that atypical antipsychotics are ineffective for eating disorders and substance abuse disorder.

• The level of evidence is mixed regarding personality disorders, and is moderate for an association of risperidone with improving PTSD."

Dr. Maher and her colleagues cautioned that most of the studies they reviewed – for example, 27 of the 38 trials of dementia and 12 of the 14 trials of anxiety – were sponsored by drug manufacturers. And they found no studies at all on the off-label use of three newer atypical antipsychotic drugs: asenapine, iloperidone, and paliperidone.

In addition, studies published after June 1, 2011, including a large randomized, control trial of risperidone for patients with military-related PTSD and symptoms resistant to selective serotonin reuptake inhibitors, were not included in the current review.

Still, evidence found in the meta-analysis should provide guidance to clinicians who are considering off-label prescribing of atypical antipsychotics, the investigators wrote.

This study was supported by the Agency for Healthcare Research and Quality, with some support from the Department of Veterans Affairs. One of Dr. Maher’s colleagues reported ties to Eli Lilly.

Atypical antipsychotics are effective in only a few of the many off-label conditions for which they are currently used, according to a meta-analysis in the Sept. 28 issue of JAMA.

In particular, there is no good evidence to support the use of atypical antipsychotics for substance abuse disorder, eating disorders, or insomnia. And the evidence for using them for posttraumatic stress disorder and personality disorders is characterized as "mixed," said Dr. Alicia Ruelaz Maher of Rand Health, Southern California Evidence-Based Practice Center, Santa Monica, and her colleagues.

Atypical antipsychotics are approved for use in schizophrenia, bipolar disorder, and, for select agents, depression. But their use has rapidly increased in recent years, and it is estimated that their off-label use doubled between 1995 and 2008.

Dr. Maher and her colleagues reviewed 2,066 articles published through May 2011 on the off-label use of aripiprazole, asenapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. For their meta-analysis, Dr. Maher and her colleagues included 162 efficacy trials and 231 trials or large observational studies that addressed adverse events (JAMA 2011;306:1359-69).

Among their findings were the following:

• "First, aripiprazole, olanzapine, and risperidone were associated with small but statistically significant benefits for the treatment of behavioral symptoms in dementia." These drugs improved psychosis, agitation, and symptoms such as hallucinations, suspiciousness, dysphoria, anxiety, aggression, disinhibition, and apathy, though they did so only to a degree "considered to be the minimum clinically observable change."

• In three large and very recent trials not included in previous meta-analyses, quetiapine showed significant benefits for generalized anxiety disorder. However, "we classified the strength of evidence for this outcome as ‘moderate,’ based on the inconsistency of results and because all [the trials] were funded by manufacturers."

• Risperidone was associated with significant improvement in OCD. But that finding was tempered by the fact there may have been publication bias affecting the pooled results.

• "The strength of evidence has decreased from moderate to low for [use of] quetiapine in patients with OCD."

• New evidence indicates that atypical antipsychotics are ineffective for eating disorders and substance abuse disorder.

• The level of evidence is mixed regarding personality disorders, and is moderate for an association of risperidone with improving PTSD."

Dr. Maher and her colleagues cautioned that most of the studies they reviewed – for example, 27 of the 38 trials of dementia and 12 of the 14 trials of anxiety – were sponsored by drug manufacturers. And they found no studies at all on the off-label use of three newer atypical antipsychotic drugs: asenapine, iloperidone, and paliperidone.

In addition, studies published after June 1, 2011, including a large randomized, control trial of risperidone for patients with military-related PTSD and symptoms resistant to selective serotonin reuptake inhibitors, were not included in the current review.

Still, evidence found in the meta-analysis should provide guidance to clinicians who are considering off-label prescribing of atypical antipsychotics, the investigators wrote.

This study was supported by the Agency for Healthcare Research and Quality, with some support from the Department of Veterans Affairs. One of Dr. Maher’s colleagues reported ties to Eli Lilly.

For 3 years, your mental health clinic has been treating Ms. J, age 23, for bipolar disorder. She is single, unemployed, lives alone, and receives Social Security disability assistance and financial support from her parents. She has been successfully maintained on aripiprazole, 15 mg/d, and citalopram, 20 mg/d, for 18 months. Six months ago she began to miss therapy sessions and physician visits.

Her parents inform Ms. J’s therapist that she is “snorting oxycontin” with her new boyfriend. At her next visit Ms. J confirms she has been struggling to manage an opioid use disorder for more than 1 year, and requests help.

After you educate her about the diagnosis, pathophysiology, and treatment of opioid addiction, she chooses to include pharmacotherapy as part of her treatment. After informed consent, Ms. J agrees to take buprenorphine and naloxone, meet with her therapist weekly, and attend twice-weekly Narcotics Anonymous (NA) meetings. Over the ensuing months she is gradually inducted onto buprenorphine and naloxone, 12 mg, shows improved insight and motivation, provides negative urine drug screens, and demonstrates increased ability to manage her recovery. Two weeks later Ms. J tells you she may be pregnant but wants to continue buprenorphine and naloxone.

Opioid use disorder (OUD) during pregnancy is among the most difficult clinical scenarios to manage. The prevalence of OUD during pregnancy is largely unknown. However, stigma against pregnant patients with OUD is substantial.¹ This article briefly summarizes identification, assessment, and treatment of OUD during pregnancy. To avoid confusion with the term “physical dependence, “ we will use “opioid use disorder” instead of “opioid dependence. “ The DSM-5 Substance Use Disorders Workgroup recommends combining abuse and dependence into a single disorder of graded clinical severity; however, this has not been finalized.²

Early identification is crucial

Early identification of OUD in pregnant women can be challenging. Self-reports underestimate use³ and shame, fear of prosecution or involvement of child welfare services, and guilt can further erode self-report. Women with OUD may have irregular menses and might not be aware of their pregnancy until several months after conception.⁴ Also, women with OUD who are maintained on opioid agonist therapies may misinterpret early signs of pregnancy—such as fatigue, nausea, vomiting, headaches, and cramps—as withdrawal symptoms and may respond by increasing their opioid dosing, thus exposing their fetus to increased drug levels. Finally, many women with OUD experience amenorrhea as a result of their stressful, unhealthy lifestyle, which may preclude pregnancy despite sexual activity. When these women later enroll in an opioid maintenance program, their endocrine function may return to normal, leading to unexpected pregnancy.⁵

Screening for OUD in pregnant patients has not been well studied. An interviewer’s nonjudgmental, empathic attitude may be more important than the specific questions he or she asks. It may be best to begin with less threatening questions and proceed to more specific questions after developing a therapeutic alliance.⁶

Chasnoff et al⁷ studied >2, 000 Medicaid-eligible pregnant patients from 9 prenatal clinics to identify risk factors for substance use during pregnancy. Alcohol or tobacco use in the month before pregnancy most differentiated current drug or alcohol use from nonuse while pregnant; however, a wide variation in use rates among patients in this study limits the generalizability of these findings. Consider OUD in women with:

• physical examination findings or history that suggests substance use or withdrawal symptoms

• positive drug test results for illicit or nonprescribed opioids

• aberrant medication-taking behaviors in those receiving prescribed opioids

• nicotine or alcohol use in the month before they knew they were pregnant

• a history of addiction-related disorders

• evidence of diseases associated with drug use, such as human immunodeficiency virus or hepatitis C

• poor prenatal care attendance

• unexplained fetal growth abnormalities.

Chasnoff et al demonstrated the reliability and effectiveness of a 1-minute, 5-item instrument (the “4 P’s Plus”) to screen for substance use, including heroin, during pregnancy (Table 1)⁸ In a study of 228 pregnant women, the overall internal consistency of this instrument was low but acceptable. More than three-quarters of patients (78%) were correctly classified as positive or negative, sensitivity was 87%, specificity was 76%, negative predictive validity was extremely high (97%), and positive predictive validity was low (36%). This low positive predictive validity may be acceptable in this population because over-identification of women at risk may be preferred to under-identification. The 4 P’s Plus identifies light and infrequent substance users who otherwise would go undetected, although it may place undue burden on providers to follow up on what later may be revealed to be a false positive screen.⁹ OUD-specific screening approaches are lacking; screening for general substance use is discussed elsewhere in the literature.¹⁰

A combination of interviewing and biologic drug screening may be more effective than either approach alone.¹¹ Drug screening should include opioids typically screened for (morphine, codeine, heroin metabolite) and those for which additional tests may be required (eg, semi-synthetics such as oxycodone and synthetics such as fentanyl). Learn your state’s civil mandates regarding drug-using pregnant women, guidelines for addiction treatment, and confidentiality provisions, especially as they relate to drug testing and mandatory reporting. Ideally, patients should be informed of these issues before they undergo drug testing or other procedures. These requirements may vary according to physician specialty or role in providing care.

Diagnosis of opioid dependence is based on DSM-IV-TR criteria; however, the proposed DSM-5 criteria for OUD may better emphasize cautions about including tolerance or withdrawal when diagnosing OUD in the setting of medically supervised and appropriate opioid use.²

Stigma against pregnant women with OUD easily can erode therapeutic efforts. Perhaps the most important element of assessment is maximizing the therapeutic alliance to ensure that the patient complies with prenatal obstetric care and maternal addiction services. Pregnancy may be an opportune time to motivate women with OUD to make a change because they may be more open to receiving help.¹² Motivational interventions are helpful for many but not all patients; the best approach to such interventions is still uncertain.¹³ Regardless of the mother’s motivation, prenatal care is fundamental.

Table 1 The ‘4P’s Plus’ screen for substance use during pregnancy

Office management

OUD-specific treatment decreases opioid use and improves birth outcomes¹⁴; however, retaining these patients in treatment can be difficult. Addressing social issues— including financial burdens, unstable living conditions, intimate partner violence, transportation difficulties, and limited access to medical and child care—can facilitate treatment.⁵ The Addiction Severity Index version tailored to women and pregnancy¹⁵ examines 7 domains of functioning (drugs, alcohol, psychological, social, medical, legal, and employment), informs treatment planning, quantifies treatment progress, and has predictive validity.¹⁶ Services are more likely to be effective if started during pregnancy as opposed to after delivery. Although detoxification is possible under carefully monitored conditions, many women relapse after detoxifying, and neonatal abstinence syndrome (NAS)—a disorder in which an addicted newborn experiences drug withdrawal—is common. Therefore, the risks of detoxification often outweigh benefits.^5,17,18

Rehabilitation services for the mother can be provided at various levels of care, including outpatient, intensive outpatient, day hospital, residential, and inpatient. Although pregnancy-specific OUD treatment is ideal, it may not be available. Clinicians should attempt to locate services that can incorporate resources for pregnant women. Providing a means for child care during treatment is paramount to compliance. Develop a plan for nonconfrontational counseling, job skills training/education, and ongoing care after delivery (including child care and transportation resources) at the onset of treatment. The length of time maintained in treatment is one of the strongest predictors of abstinence.⁵

Pregnant women with OUD should be screened for comorbid medical, obstetric, and psychiatric complications and referred accordingly (Table 2 and Table 3).⁶ Coordination among the patient’s psychiatrist, primary care provider, and obstetrician/gynecologist is essential. Programs that integrate these approaches into a single treatment team may be ideal. Although pregnancy per se may not be associated with higher risk of mental disorders, the risk of major depressive disorder may be increased during the postpartum period.¹⁹ Young, unmarried women with recent stressful life events, complicated pregnancies, and poor overall health may face a significantly increased risk of psychiatric illness during pregnancy.¹⁹ Patients whose opioid use has caused pregnancy complications may experience guilt and grief.

Increased education and screening for substance use as the pregnancy approaches term is necessary because patients may mistake early labor for symptoms of opioid withdrawal or worry that delivery room pain management will be inadequate and therefore relapse. Among pregnant women with addiction, preterm labor may be most common in those with OUD.¹² 

Table 2 Medical complications common to pregnancy and substance abuse

Table 3 Obstetric complications in women with addiction disorders

Opioid agonist therapy

Obstetric complications in women with OUD may be related to rapid, frequent fluctuations of opioid blood levels during intoxication and withdrawal. Therefore, the first goal of pharmacotherapy is to reduce physical stress associated with cycling opioid blood levels. Opioid agonist medications can be extremely effective. Opioid agonist treatment for pregnant patients is similar to that of nonpregnant patients but includes pregnancy-specific objectives (Table 4).²⁰

Few anti-relapse medications have been studied in pregnant patients. Pharmacotherapies for OUD include methadone and buprenorphine. In our experience, opioid antagonists such as naltrexone typically would not be considered for pregnant patients because:

• their expected efficacy in reducing relapse in pregnant patients is lower than that of other medications

• their expected risk for inducing withdrawal is higher compared with methadone or buprenorphine

• research on the use of naltrexone during pregnancy is lacking.

Methadone has been used to treat OUD during pregnancy since the late 1970s.⁵ It requires adherence to strict federal regulations and is FDA pregnancy class C (animal reproduction studies have shown an adverse effect on the fetus and there are no adequate well-controlled studies in humans, but potential benefits may warrant use in pregnant women despite potential risks). Pregnant women have been safely maintained on methadone without adverse long-term maternal or fetal effects, and the National Institutes of Health recommends it as the standard of care for pregnant women with OUD. A woman steadily maintained on methadone is more likely to have a healthy pregnancy and infant than a woman who uses alcohol or other drugs.²¹ Further, the structure and services of methadone maintenance treatment can improve compliance with prenatal care and help prepare patients for parental responsibilities.

Fluctuating blood opioid levels are minimized when methadone dosage is individually determined. Dosages should be based on a woman’s stage of pregnancy, relapse risk, pre-pregnancy methadone dose, experience with methadone, and clinical history. Some women experience lowered methadone blood levels during pregnancy because of increased fluid space, a larger tissue reservoir that can store methadone, and increased drug metabolism by both placenta and fetus. As a result, increased or split (twice daily) dosing may be indicated.^22-24

Buprenorphine is FDA pregnancy class C. Although not approved for use during pregnancy, it has been used successfully for pregnant patients with OUD.^12,25 It is a partial agonist of the mu opioid receptor and an antagonist of the kappa opioid receptor, which may reduce its abuse liability and NAS severity.

The few randomized clinical trials comparing methadone with buprenorphine during pregnancy suggest that buprenorphine is not inferior to methadone in safety and discomfort of induction from a short-acting opioid, nor in outcome measures assessing NAS and maternal and neonatal safety.^26,27 Results from the recent Maternal Opioid Treatment: Human Experimental Research project suggest that buprenorphine may have some advantages over methadone in pregnancy. Buprenorphine-maintained neonates may need less morphine, have shorter hospital stays, and require shorter treatment for NAS.²⁸ However, treatment retention may be lower for buprenorphine-maintained mothers; any resultant long-term consequences on maternal and child health are as yet unexplored. These findings require replication.

Methadone and buprenorphine are not interchangeable. Many patients maintained on methadone do not respond optimally to buprenorphine. Clinics that dispense maintenance methadone are required to provide counseling services and random drug testing; these requirements do not apply to physicians who prescribe buprenorphine. Moreover, in our experience buprenorphine at times has been prescribed without close regard to psychosocial issues, adequate random drug testing, or coordination of care with other providers.

In pregnant patients, buprenorphine is preferred over buprenorphine and naloxone to avoid fetal exposure to naloxone, which may cause intrauterine withdrawal and maternal-fetal hormonal changes. To reduce abuse or diversion, patients should undergo drug testing to ensure buprenorphine is present, smaller prescriptions may be provided, and tablets can be counted. Limited data suggests buprenorphine is not teratogenic. Some data show low placental transfer of buprenorphine, thereby limiting fetal exposure and lowering risk for intrauterine growth restriction.²⁹ 

Table 4 Opioid agonist treatment objectives for addicted patients who are pregnant

 Delivery and postnatal care

^{Compared with those not in treatment, women who are engaged in a multidisciplinary treatment program at the time of delivery demonstrated higher gestational age, increased birth weights, and lower rates of neonatal ICU admissions. They also realized a cost savings of $4, 644 per mother-infant pair.30}

^{During delivery, pain medication should not be withheld solely because a pregnant woman has a history of addiction-related disorders; these women are subject to pain during delivery as much as other women. Avoid using mixed agonists/antagonists such as nalbuphine or butorphanol in women receiving opioid maintenance medication. Labor and delivery pain management for a pregnant patient maintained on opioid agonist therapies is discussed elsewhere in the literature.31 Every effort should be made to ensure that the mother remains in treatment through delivery and beyond.}

^{To read about advising women with OUD on the benefits and risks of breastfeeding while receiving opioid agonist maintenance treatment, see the Box below.}

CASE CONTINUED: Medication change

^{Ms. J’s boyfriend has left her and her parents have not readily accepted her pregnancy and need for support. She continues to attend NA meetings and weekly therapy. After educating her about the differences between buprenorphine and buprenorphine and naloxone in relation to risk, benefits, and side effects, you switch Ms. J to buprenorphine, 12 mg/d, while maintaining her on aripiprazole and citalopram. She consents to exchanging information about her medical, mental health, and addiction-related treatment with her primary care provider, who helps locate an obstetrician/gynecologist comfortable with her OUD and buprenorphine. Ms. J’s therapist helps link her with social services agencies to ensure prenatal care, assist with removing barriers to care, and plan for her needs as a parent.}

^{After checking your state’s mandates, you determine you are not required to report Ms. J’s drug testing results. Ms. J’s ongoing drug testing shows the presence of buprenorphine and the absence of other opioids and all drugs of abuse.}

^{Ms. J’s delivery is uncomplicated medically; however, family, financial, and parental role issues remain problematic. Encouraging her involvement in therapy and social services as part of her continued buprenorphine prescribing proves beneficial.}

Related Resources

• ^{Jones HE, Martin PR, Heil SH, et al. Treatment of opioid dependent pregnant women: clinical and research issues. J Subst Abuse Treat. 2008; 35(3): 245-259.}

• ^{Johnson RE, Jones HE, Fischer G. Use of buprenorphine in pregnancy: patient management and effects on the neonate. Drug Alcohol Depend. 2003; 70(suppl 1 ): S87-S101.}

• ^{Velez M, Jansson LM. The opioid dependent mother and the newborn dyad: nonpharmacologic care. J Addict Med. 2008; 2(3): 113-120.}

Drug Brand Names

^{Aripiprazole • Abilify}

Buprenorphine and naloxone •Suboxone

Buprenorphine • Subutex

Butorphanol • Stadol

Citalopram • Celexa

Fentanyl • Duragesic, Sublimaze, others

Methadone • Dolophine

Naloxone • Narcan

Naltrexone • ReVia

Nalbuphine • Nubain

Oxycodone • Oxycontin

Disclosures

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

^{Dr. Fernandez’ time toward this project was funded by the University Hospital/University of Cincinnati Addiction Psychiatry Fellowship Training Program operated by the Center for Treatment, Research, and Education in Addictive Disorders (CeTREAD), Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati and by the Veterans Affairs Medical Center, Cincinnati, OH.}

^{The statements in this publication do not necessarily reflect the views or opinions of the Department of Veterans Affairs, the United States Government, or Opiate Addiction Recovery Services.}

For 3 years, your mental health clinic has been treating Ms. J, age 23, for bipolar disorder. She is single, unemployed, lives alone, and receives Social Security disability assistance and financial support from her parents. She has been successfully maintained on aripiprazole, 15 mg/d, and citalopram, 20 mg/d, for 18 months. Six months ago she began to miss therapy sessions and physician visits.

Her parents inform Ms. J’s therapist that she is “snorting oxycontin” with her new boyfriend. At her next visit Ms. J confirms she has been struggling to manage an opioid use disorder for more than 1 year, and requests help.

After you educate her about the diagnosis, pathophysiology, and treatment of opioid addiction, she chooses to include pharmacotherapy as part of her treatment. After informed consent, Ms. J agrees to take buprenorphine and naloxone, meet with her therapist weekly, and attend twice-weekly Narcotics Anonymous (NA) meetings. Over the ensuing months she is gradually inducted onto buprenorphine and naloxone, 12 mg, shows improved insight and motivation, provides negative urine drug screens, and demonstrates increased ability to manage her recovery. Two weeks later Ms. J tells you she may be pregnant but wants to continue buprenorphine and naloxone.

Opioid use disorder (OUD) during pregnancy is among the most difficult clinical scenarios to manage. The prevalence of OUD during pregnancy is largely unknown. However, stigma against pregnant patients with OUD is substantial.¹ This article briefly summarizes identification, assessment, and treatment of OUD during pregnancy. To avoid confusion with the term “physical dependence, “ we will use “opioid use disorder” instead of “opioid dependence. “ The DSM-5 Substance Use Disorders Workgroup recommends combining abuse and dependence into a single disorder of graded clinical severity; however, this has not been finalized.²

Early identification is crucial

Early identification of OUD in pregnant women can be challenging. Self-reports underestimate use³ and shame, fear of prosecution or involvement of child welfare services, and guilt can further erode self-report. Women with OUD may have irregular menses and might not be aware of their pregnancy until several months after conception.⁴ Also, women with OUD who are maintained on opioid agonist therapies may misinterpret early signs of pregnancy—such as fatigue, nausea, vomiting, headaches, and cramps—as withdrawal symptoms and may respond by increasing their opioid dosing, thus exposing their fetus to increased drug levels. Finally, many women with OUD experience amenorrhea as a result of their stressful, unhealthy lifestyle, which may preclude pregnancy despite sexual activity. When these women later enroll in an opioid maintenance program, their endocrine function may return to normal, leading to unexpected pregnancy.⁵

Screening for OUD in pregnant patients has not been well studied. An interviewer’s nonjudgmental, empathic attitude may be more important than the specific questions he or she asks. It may be best to begin with less threatening questions and proceed to more specific questions after developing a therapeutic alliance.⁶

Chasnoff et al⁷ studied >2, 000 Medicaid-eligible pregnant patients from 9 prenatal clinics to identify risk factors for substance use during pregnancy. Alcohol or tobacco use in the month before pregnancy most differentiated current drug or alcohol use from nonuse while pregnant; however, a wide variation in use rates among patients in this study limits the generalizability of these findings. Consider OUD in women with:

• physical examination findings or history that suggests substance use or withdrawal symptoms

• positive drug test results for illicit or nonprescribed opioids

• aberrant medication-taking behaviors in those receiving prescribed opioids

• nicotine or alcohol use in the month before they knew they were pregnant

• a history of addiction-related disorders

• evidence of diseases associated with drug use, such as human immunodeficiency virus or hepatitis C

• poor prenatal care attendance

• unexplained fetal growth abnormalities.

Chasnoff et al demonstrated the reliability and effectiveness of a 1-minute, 5-item instrument (the “4 P’s Plus”) to screen for substance use, including heroin, during pregnancy (Table 1)⁸ In a study of 228 pregnant women, the overall internal consistency of this instrument was low but acceptable. More than three-quarters of patients (78%) were correctly classified as positive or negative, sensitivity was 87%, specificity was 76%, negative predictive validity was extremely high (97%), and positive predictive validity was low (36%). This low positive predictive validity may be acceptable in this population because over-identification of women at risk may be preferred to under-identification. The 4 P’s Plus identifies light and infrequent substance users who otherwise would go undetected, although it may place undue burden on providers to follow up on what later may be revealed to be a false positive screen.⁹ OUD-specific screening approaches are lacking; screening for general substance use is discussed elsewhere in the literature.¹⁰

A combination of interviewing and biologic drug screening may be more effective than either approach alone.¹¹ Drug screening should include opioids typically screened for (morphine, codeine, heroin metabolite) and those for which additional tests may be required (eg, semi-synthetics such as oxycodone and synthetics such as fentanyl). Learn your state’s civil mandates regarding drug-using pregnant women, guidelines for addiction treatment, and confidentiality provisions, especially as they relate to drug testing and mandatory reporting. Ideally, patients should be informed of these issues before they undergo drug testing or other procedures. These requirements may vary according to physician specialty or role in providing care.

Diagnosis of opioid dependence is based on DSM-IV-TR criteria; however, the proposed DSM-5 criteria for OUD may better emphasize cautions about including tolerance or withdrawal when diagnosing OUD in the setting of medically supervised and appropriate opioid use.²

Stigma against pregnant women with OUD easily can erode therapeutic efforts. Perhaps the most important element of assessment is maximizing the therapeutic alliance to ensure that the patient complies with prenatal obstetric care and maternal addiction services. Pregnancy may be an opportune time to motivate women with OUD to make a change because they may be more open to receiving help.¹² Motivational interventions are helpful for many but not all patients; the best approach to such interventions is still uncertain.¹³ Regardless of the mother’s motivation, prenatal care is fundamental.

Table 1 The ‘4P’s Plus’ screen for substance use during pregnancy

Office management

OUD-specific treatment decreases opioid use and improves birth outcomes¹⁴; however, retaining these patients in treatment can be difficult. Addressing social issues— including financial burdens, unstable living conditions, intimate partner violence, transportation difficulties, and limited access to medical and child care—can facilitate treatment.⁵ The Addiction Severity Index version tailored to women and pregnancy¹⁵ examines 7 domains of functioning (drugs, alcohol, psychological, social, medical, legal, and employment), informs treatment planning, quantifies treatment progress, and has predictive validity.¹⁶ Services are more likely to be effective if started during pregnancy as opposed to after delivery. Although detoxification is possible under carefully monitored conditions, many women relapse after detoxifying, and neonatal abstinence syndrome (NAS)—a disorder in which an addicted newborn experiences drug withdrawal—is common. Therefore, the risks of detoxification often outweigh benefits.^5,17,18

Rehabilitation services for the mother can be provided at various levels of care, including outpatient, intensive outpatient, day hospital, residential, and inpatient. Although pregnancy-specific OUD treatment is ideal, it may not be available. Clinicians should attempt to locate services that can incorporate resources for pregnant women. Providing a means for child care during treatment is paramount to compliance. Develop a plan for nonconfrontational counseling, job skills training/education, and ongoing care after delivery (including child care and transportation resources) at the onset of treatment. The length of time maintained in treatment is one of the strongest predictors of abstinence.⁵

Pregnant women with OUD should be screened for comorbid medical, obstetric, and psychiatric complications and referred accordingly (Table 2 and Table 3).⁶ Coordination among the patient’s psychiatrist, primary care provider, and obstetrician/gynecologist is essential. Programs that integrate these approaches into a single treatment team may be ideal. Although pregnancy per se may not be associated with higher risk of mental disorders, the risk of major depressive disorder may be increased during the postpartum period.¹⁹ Young, unmarried women with recent stressful life events, complicated pregnancies, and poor overall health may face a significantly increased risk of psychiatric illness during pregnancy.¹⁹ Patients whose opioid use has caused pregnancy complications may experience guilt and grief.

Increased education and screening for substance use as the pregnancy approaches term is necessary because patients may mistake early labor for symptoms of opioid withdrawal or worry that delivery room pain management will be inadequate and therefore relapse. Among pregnant women with addiction, preterm labor may be most common in those with OUD.¹² 

Table 2 Medical complications common to pregnancy and substance abuse

Table 3 Obstetric complications in women with addiction disorders

Opioid agonist therapy

Obstetric complications in women with OUD may be related to rapid, frequent fluctuations of opioid blood levels during intoxication and withdrawal. Therefore, the first goal of pharmacotherapy is to reduce physical stress associated with cycling opioid blood levels. Opioid agonist medications can be extremely effective. Opioid agonist treatment for pregnant patients is similar to that of nonpregnant patients but includes pregnancy-specific objectives (Table 4).²⁰

Few anti-relapse medications have been studied in pregnant patients. Pharmacotherapies for OUD include methadone and buprenorphine. In our experience, opioid antagonists such as naltrexone typically would not be considered for pregnant patients because:

• their expected efficacy in reducing relapse in pregnant patients is lower than that of other medications

• their expected risk for inducing withdrawal is higher compared with methadone or buprenorphine

• research on the use of naltrexone during pregnancy is lacking.

Methadone has been used to treat OUD during pregnancy since the late 1970s.⁵ It requires adherence to strict federal regulations and is FDA pregnancy class C (animal reproduction studies have shown an adverse effect on the fetus and there are no adequate well-controlled studies in humans, but potential benefits may warrant use in pregnant women despite potential risks). Pregnant women have been safely maintained on methadone without adverse long-term maternal or fetal effects, and the National Institutes of Health recommends it as the standard of care for pregnant women with OUD. A woman steadily maintained on methadone is more likely to have a healthy pregnancy and infant than a woman who uses alcohol or other drugs.²¹ Further, the structure and services of methadone maintenance treatment can improve compliance with prenatal care and help prepare patients for parental responsibilities.

Fluctuating blood opioid levels are minimized when methadone dosage is individually determined. Dosages should be based on a woman’s stage of pregnancy, relapse risk, pre-pregnancy methadone dose, experience with methadone, and clinical history. Some women experience lowered methadone blood levels during pregnancy because of increased fluid space, a larger tissue reservoir that can store methadone, and increased drug metabolism by both placenta and fetus. As a result, increased or split (twice daily) dosing may be indicated.^22-24

Buprenorphine is FDA pregnancy class C. Although not approved for use during pregnancy, it has been used successfully for pregnant patients with OUD.^12,25 It is a partial agonist of the mu opioid receptor and an antagonist of the kappa opioid receptor, which may reduce its abuse liability and NAS severity.

The few randomized clinical trials comparing methadone with buprenorphine during pregnancy suggest that buprenorphine is not inferior to methadone in safety and discomfort of induction from a short-acting opioid, nor in outcome measures assessing NAS and maternal and neonatal safety.^26,27 Results from the recent Maternal Opioid Treatment: Human Experimental Research project suggest that buprenorphine may have some advantages over methadone in pregnancy. Buprenorphine-maintained neonates may need less morphine, have shorter hospital stays, and require shorter treatment for NAS.²⁸ However, treatment retention may be lower for buprenorphine-maintained mothers; any resultant long-term consequences on maternal and child health are as yet unexplored. These findings require replication.

Methadone and buprenorphine are not interchangeable. Many patients maintained on methadone do not respond optimally to buprenorphine. Clinics that dispense maintenance methadone are required to provide counseling services and random drug testing; these requirements do not apply to physicians who prescribe buprenorphine. Moreover, in our experience buprenorphine at times has been prescribed without close regard to psychosocial issues, adequate random drug testing, or coordination of care with other providers.

In pregnant patients, buprenorphine is preferred over buprenorphine and naloxone to avoid fetal exposure to naloxone, which may cause intrauterine withdrawal and maternal-fetal hormonal changes. To reduce abuse or diversion, patients should undergo drug testing to ensure buprenorphine is present, smaller prescriptions may be provided, and tablets can be counted. Limited data suggests buprenorphine is not teratogenic. Some data show low placental transfer of buprenorphine, thereby limiting fetal exposure and lowering risk for intrauterine growth restriction.²⁹ 

Table 4 Opioid agonist treatment objectives for addicted patients who are pregnant

 Delivery and postnatal care

^{Compared with those not in treatment, women who are engaged in a multidisciplinary treatment program at the time of delivery demonstrated higher gestational age, increased birth weights, and lower rates of neonatal ICU admissions. They also realized a cost savings of $4, 644 per mother-infant pair.30}

^{During delivery, pain medication should not be withheld solely because a pregnant woman has a history of addiction-related disorders; these women are subject to pain during delivery as much as other women. Avoid using mixed agonists/antagonists such as nalbuphine or butorphanol in women receiving opioid maintenance medication. Labor and delivery pain management for a pregnant patient maintained on opioid agonist therapies is discussed elsewhere in the literature.31 Every effort should be made to ensure that the mother remains in treatment through delivery and beyond.}

^{To read about advising women with OUD on the benefits and risks of breastfeeding while receiving opioid agonist maintenance treatment, see the Box below.}

CASE CONTINUED: Medication change

^{Ms. J’s boyfriend has left her and her parents have not readily accepted her pregnancy and need for support. She continues to attend NA meetings and weekly therapy. After educating her about the differences between buprenorphine and buprenorphine and naloxone in relation to risk, benefits, and side effects, you switch Ms. J to buprenorphine, 12 mg/d, while maintaining her on aripiprazole and citalopram. She consents to exchanging information about her medical, mental health, and addiction-related treatment with her primary care provider, who helps locate an obstetrician/gynecologist comfortable with her OUD and buprenorphine. Ms. J’s therapist helps link her with social services agencies to ensure prenatal care, assist with removing barriers to care, and plan for her needs as a parent.}

^{After checking your state’s mandates, you determine you are not required to report Ms. J’s drug testing results. Ms. J’s ongoing drug testing shows the presence of buprenorphine and the absence of other opioids and all drugs of abuse.}

^{Ms. J’s delivery is uncomplicated medically; however, family, financial, and parental role issues remain problematic. Encouraging her involvement in therapy and social services as part of her continued buprenorphine prescribing proves beneficial.}

Related Resources

• ^{Jones HE, Martin PR, Heil SH, et al. Treatment of opioid dependent pregnant women: clinical and research issues. J Subst Abuse Treat. 2008; 35(3): 245-259.}

• ^{Johnson RE, Jones HE, Fischer G. Use of buprenorphine in pregnancy: patient management and effects on the neonate. Drug Alcohol Depend. 2003; 70(suppl 1 ): S87-S101.}

• ^{Velez M, Jansson LM. The opioid dependent mother and the newborn dyad: nonpharmacologic care. J Addict Med. 2008; 2(3): 113-120.}

Drug Brand Names

^{Aripiprazole • Abilify}

Buprenorphine and naloxone •Suboxone

Buprenorphine • Subutex

Butorphanol • Stadol

Citalopram • Celexa

Fentanyl • Duragesic, Sublimaze, others

Methadone • Dolophine

Naloxone • Narcan

Naltrexone • ReVia

Nalbuphine • Nubain

Oxycodone • Oxycontin

Disclosures

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

^{Dr. Fernandez’ time toward this project was funded by the University Hospital/University of Cincinnati Addiction Psychiatry Fellowship Training Program operated by the Center for Treatment, Research, and Education in Addictive Disorders (CeTREAD), Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati and by the Veterans Affairs Medical Center, Cincinnati, OH.}

^{The statements in this publication do not necessarily reflect the views or opinions of the Department of Veterans Affairs, the United States Government, or Opiate Addiction Recovery Services.}

For 3 years, your mental health clinic has been treating Ms. J, age 23, for bipolar disorder. She is single, unemployed, lives alone, and receives Social Security disability assistance and financial support from her parents. She has been successfully maintained on aripiprazole, 15 mg/d, and citalopram, 20 mg/d, for 18 months. Six months ago she began to miss therapy sessions and physician visits.

Her parents inform Ms. J’s therapist that she is “snorting oxycontin” with her new boyfriend. At her next visit Ms. J confirms she has been struggling to manage an opioid use disorder for more than 1 year, and requests help.

After you educate her about the diagnosis, pathophysiology, and treatment of opioid addiction, she chooses to include pharmacotherapy as part of her treatment. After informed consent, Ms. J agrees to take buprenorphine and naloxone, meet with her therapist weekly, and attend twice-weekly Narcotics Anonymous (NA) meetings. Over the ensuing months she is gradually inducted onto buprenorphine and naloxone, 12 mg, shows improved insight and motivation, provides negative urine drug screens, and demonstrates increased ability to manage her recovery. Two weeks later Ms. J tells you she may be pregnant but wants to continue buprenorphine and naloxone.

Opioid use disorder (OUD) during pregnancy is among the most difficult clinical scenarios to manage. The prevalence of OUD during pregnancy is largely unknown. However, stigma against pregnant patients with OUD is substantial.¹ This article briefly summarizes identification, assessment, and treatment of OUD during pregnancy. To avoid confusion with the term “physical dependence, “ we will use “opioid use disorder” instead of “opioid dependence. “ The DSM-5 Substance Use Disorders Workgroup recommends combining abuse and dependence into a single disorder of graded clinical severity; however, this has not been finalized.²

Early identification is crucial

Early identification of OUD in pregnant women can be challenging. Self-reports underestimate use³ and shame, fear of prosecution or involvement of child welfare services, and guilt can further erode self-report. Women with OUD may have irregular menses and might not be aware of their pregnancy until several months after conception.⁴ Also, women with OUD who are maintained on opioid agonist therapies may misinterpret early signs of pregnancy—such as fatigue, nausea, vomiting, headaches, and cramps—as withdrawal symptoms and may respond by increasing their opioid dosing, thus exposing their fetus to increased drug levels. Finally, many women with OUD experience amenorrhea as a result of their stressful, unhealthy lifestyle, which may preclude pregnancy despite sexual activity. When these women later enroll in an opioid maintenance program, their endocrine function may return to normal, leading to unexpected pregnancy.⁵

Screening for OUD in pregnant patients has not been well studied. An interviewer’s nonjudgmental, empathic attitude may be more important than the specific questions he or she asks. It may be best to begin with less threatening questions and proceed to more specific questions after developing a therapeutic alliance.⁶

Chasnoff et al⁷ studied >2, 000 Medicaid-eligible pregnant patients from 9 prenatal clinics to identify risk factors for substance use during pregnancy. Alcohol or tobacco use in the month before pregnancy most differentiated current drug or alcohol use from nonuse while pregnant; however, a wide variation in use rates among patients in this study limits the generalizability of these findings. Consider OUD in women with:

• physical examination findings or history that suggests substance use or withdrawal symptoms

• positive drug test results for illicit or nonprescribed opioids

• aberrant medication-taking behaviors in those receiving prescribed opioids

• nicotine or alcohol use in the month before they knew they were pregnant

• a history of addiction-related disorders

• evidence of diseases associated with drug use, such as human immunodeficiency virus or hepatitis C

• poor prenatal care attendance

• unexplained fetal growth abnormalities.

Chasnoff et al demonstrated the reliability and effectiveness of a 1-minute, 5-item instrument (the “4 P’s Plus”) to screen for substance use, including heroin, during pregnancy (Table 1)⁸ In a study of 228 pregnant women, the overall internal consistency of this instrument was low but acceptable. More than three-quarters of patients (78%) were correctly classified as positive or negative, sensitivity was 87%, specificity was 76%, negative predictive validity was extremely high (97%), and positive predictive validity was low (36%). This low positive predictive validity may be acceptable in this population because over-identification of women at risk may be preferred to under-identification. The 4 P’s Plus identifies light and infrequent substance users who otherwise would go undetected, although it may place undue burden on providers to follow up on what later may be revealed to be a false positive screen.⁹ OUD-specific screening approaches are lacking; screening for general substance use is discussed elsewhere in the literature.¹⁰

A combination of interviewing and biologic drug screening may be more effective than either approach alone.¹¹ Drug screening should include opioids typically screened for (morphine, codeine, heroin metabolite) and those for which additional tests may be required (eg, semi-synthetics such as oxycodone and synthetics such as fentanyl). Learn your state’s civil mandates regarding drug-using pregnant women, guidelines for addiction treatment, and confidentiality provisions, especially as they relate to drug testing and mandatory reporting. Ideally, patients should be informed of these issues before they undergo drug testing or other procedures. These requirements may vary according to physician specialty or role in providing care.

Diagnosis of opioid dependence is based on DSM-IV-TR criteria; however, the proposed DSM-5 criteria for OUD may better emphasize cautions about including tolerance or withdrawal when diagnosing OUD in the setting of medically supervised and appropriate opioid use.²

Stigma against pregnant women with OUD easily can erode therapeutic efforts. Perhaps the most important element of assessment is maximizing the therapeutic alliance to ensure that the patient complies with prenatal obstetric care and maternal addiction services. Pregnancy may be an opportune time to motivate women with OUD to make a change because they may be more open to receiving help.¹² Motivational interventions are helpful for many but not all patients; the best approach to such interventions is still uncertain.¹³ Regardless of the mother’s motivation, prenatal care is fundamental.

Table 1 The ‘4P’s Plus’ screen for substance use during pregnancy

Office management

OUD-specific treatment decreases opioid use and improves birth outcomes¹⁴; however, retaining these patients in treatment can be difficult. Addressing social issues— including financial burdens, unstable living conditions, intimate partner violence, transportation difficulties, and limited access to medical and child care—can facilitate treatment.⁵ The Addiction Severity Index version tailored to women and pregnancy¹⁵ examines 7 domains of functioning (drugs, alcohol, psychological, social, medical, legal, and employment), informs treatment planning, quantifies treatment progress, and has predictive validity.¹⁶ Services are more likely to be effective if started during pregnancy as opposed to after delivery. Although detoxification is possible under carefully monitored conditions, many women relapse after detoxifying, and neonatal abstinence syndrome (NAS)—a disorder in which an addicted newborn experiences drug withdrawal—is common. Therefore, the risks of detoxification often outweigh benefits.^5,17,18

Rehabilitation services for the mother can be provided at various levels of care, including outpatient, intensive outpatient, day hospital, residential, and inpatient. Although pregnancy-specific OUD treatment is ideal, it may not be available. Clinicians should attempt to locate services that can incorporate resources for pregnant women. Providing a means for child care during treatment is paramount to compliance. Develop a plan for nonconfrontational counseling, job skills training/education, and ongoing care after delivery (including child care and transportation resources) at the onset of treatment. The length of time maintained in treatment is one of the strongest predictors of abstinence.⁵

Pregnant women with OUD should be screened for comorbid medical, obstetric, and psychiatric complications and referred accordingly (Table 2 and Table 3).⁶ Coordination among the patient’s psychiatrist, primary care provider, and obstetrician/gynecologist is essential. Programs that integrate these approaches into a single treatment team may be ideal. Although pregnancy per se may not be associated with higher risk of mental disorders, the risk of major depressive disorder may be increased during the postpartum period.¹⁹ Young, unmarried women with recent stressful life events, complicated pregnancies, and poor overall health may face a significantly increased risk of psychiatric illness during pregnancy.¹⁹ Patients whose opioid use has caused pregnancy complications may experience guilt and grief.

Increased education and screening for substance use as the pregnancy approaches term is necessary because patients may mistake early labor for symptoms of opioid withdrawal or worry that delivery room pain management will be inadequate and therefore relapse. Among pregnant women with addiction, preterm labor may be most common in those with OUD.¹² 

Table 2 Medical complications common to pregnancy and substance abuse

Table 3 Obstetric complications in women with addiction disorders

Opioid agonist therapy

Obstetric complications in women with OUD may be related to rapid, frequent fluctuations of opioid blood levels during intoxication and withdrawal. Therefore, the first goal of pharmacotherapy is to reduce physical stress associated with cycling opioid blood levels. Opioid agonist medications can be extremely effective. Opioid agonist treatment for pregnant patients is similar to that of nonpregnant patients but includes pregnancy-specific objectives (Table 4).²⁰

Few anti-relapse medications have been studied in pregnant patients. Pharmacotherapies for OUD include methadone and buprenorphine. In our experience, opioid antagonists such as naltrexone typically would not be considered for pregnant patients because:

• their expected efficacy in reducing relapse in pregnant patients is lower than that of other medications

• their expected risk for inducing withdrawal is higher compared with methadone or buprenorphine

• research on the use of naltrexone during pregnancy is lacking.

Methadone has been used to treat OUD during pregnancy since the late 1970s.⁵ It requires adherence to strict federal regulations and is FDA pregnancy class C (animal reproduction studies have shown an adverse effect on the fetus and there are no adequate well-controlled studies in humans, but potential benefits may warrant use in pregnant women despite potential risks). Pregnant women have been safely maintained on methadone without adverse long-term maternal or fetal effects, and the National Institutes of Health recommends it as the standard of care for pregnant women with OUD. A woman steadily maintained on methadone is more likely to have a healthy pregnancy and infant than a woman who uses alcohol or other drugs.²¹ Further, the structure and services of methadone maintenance treatment can improve compliance with prenatal care and help prepare patients for parental responsibilities.

Fluctuating blood opioid levels are minimized when methadone dosage is individually determined. Dosages should be based on a woman’s stage of pregnancy, relapse risk, pre-pregnancy methadone dose, experience with methadone, and clinical history. Some women experience lowered methadone blood levels during pregnancy because of increased fluid space, a larger tissue reservoir that can store methadone, and increased drug metabolism by both placenta and fetus. As a result, increased or split (twice daily) dosing may be indicated.^22-24

Buprenorphine is FDA pregnancy class C. Although not approved for use during pregnancy, it has been used successfully for pregnant patients with OUD.^12,25 It is a partial agonist of the mu opioid receptor and an antagonist of the kappa opioid receptor, which may reduce its abuse liability and NAS severity.

The few randomized clinical trials comparing methadone with buprenorphine during pregnancy suggest that buprenorphine is not inferior to methadone in safety and discomfort of induction from a short-acting opioid, nor in outcome measures assessing NAS and maternal and neonatal safety.^26,27 Results from the recent Maternal Opioid Treatment: Human Experimental Research project suggest that buprenorphine may have some advantages over methadone in pregnancy. Buprenorphine-maintained neonates may need less morphine, have shorter hospital stays, and require shorter treatment for NAS.²⁸ However, treatment retention may be lower for buprenorphine-maintained mothers; any resultant long-term consequences on maternal and child health are as yet unexplored. These findings require replication.

Methadone and buprenorphine are not interchangeable. Many patients maintained on methadone do not respond optimally to buprenorphine. Clinics that dispense maintenance methadone are required to provide counseling services and random drug testing; these requirements do not apply to physicians who prescribe buprenorphine. Moreover, in our experience buprenorphine at times has been prescribed without close regard to psychosocial issues, adequate random drug testing, or coordination of care with other providers.

In pregnant patients, buprenorphine is preferred over buprenorphine and naloxone to avoid fetal exposure to naloxone, which may cause intrauterine withdrawal and maternal-fetal hormonal changes. To reduce abuse or diversion, patients should undergo drug testing to ensure buprenorphine is present, smaller prescriptions may be provided, and tablets can be counted. Limited data suggests buprenorphine is not teratogenic. Some data show low placental transfer of buprenorphine, thereby limiting fetal exposure and lowering risk for intrauterine growth restriction.²⁹ 

Table 4 Opioid agonist treatment objectives for addicted patients who are pregnant

 Delivery and postnatal care

^{Compared with those not in treatment, women who are engaged in a multidisciplinary treatment program at the time of delivery demonstrated higher gestational age, increased birth weights, and lower rates of neonatal ICU admissions. They also realized a cost savings of $4, 644 per mother-infant pair.30}

^{During delivery, pain medication should not be withheld solely because a pregnant woman has a history of addiction-related disorders; these women are subject to pain during delivery as much as other women. Avoid using mixed agonists/antagonists such as nalbuphine or butorphanol in women receiving opioid maintenance medication. Labor and delivery pain management for a pregnant patient maintained on opioid agonist therapies is discussed elsewhere in the literature.31 Every effort should be made to ensure that the mother remains in treatment through delivery and beyond.}

^{To read about advising women with OUD on the benefits and risks of breastfeeding while receiving opioid agonist maintenance treatment, see the Box below.}

CASE CONTINUED: Medication change

^{Ms. J’s boyfriend has left her and her parents have not readily accepted her pregnancy and need for support. She continues to attend NA meetings and weekly therapy. After educating her about the differences between buprenorphine and buprenorphine and naloxone in relation to risk, benefits, and side effects, you switch Ms. J to buprenorphine, 12 mg/d, while maintaining her on aripiprazole and citalopram. She consents to exchanging information about her medical, mental health, and addiction-related treatment with her primary care provider, who helps locate an obstetrician/gynecologist comfortable with her OUD and buprenorphine. Ms. J’s therapist helps link her with social services agencies to ensure prenatal care, assist with removing barriers to care, and plan for her needs as a parent.}

^{After checking your state’s mandates, you determine you are not required to report Ms. J’s drug testing results. Ms. J’s ongoing drug testing shows the presence of buprenorphine and the absence of other opioids and all drugs of abuse.}

^{Ms. J’s delivery is uncomplicated medically; however, family, financial, and parental role issues remain problematic. Encouraging her involvement in therapy and social services as part of her continued buprenorphine prescribing proves beneficial.}

Related Resources

• ^{Jones HE, Martin PR, Heil SH, et al. Treatment of opioid dependent pregnant women: clinical and research issues. J Subst Abuse Treat. 2008; 35(3): 245-259.}

• ^{Johnson RE, Jones HE, Fischer G. Use of buprenorphine in pregnancy: patient management and effects on the neonate. Drug Alcohol Depend. 2003; 70(suppl 1 ): S87-S101.}

• ^{Velez M, Jansson LM. The opioid dependent mother and the newborn dyad: nonpharmacologic care. J Addict Med. 2008; 2(3): 113-120.}

Drug Brand Names

^{Aripiprazole • Abilify}

Buprenorphine and naloxone •Suboxone

Buprenorphine • Subutex

Butorphanol • Stadol

Citalopram • Celexa

Fentanyl • Duragesic, Sublimaze, others

Methadone • Dolophine

Naloxone • Narcan

Naltrexone • ReVia

Nalbuphine • Nubain

Oxycodone • Oxycontin

Disclosures

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

^{Dr. Fernandez’ time toward this project was funded by the University Hospital/University of Cincinnati Addiction Psychiatry Fellowship Training Program operated by the Center for Treatment, Research, and Education in Addictive Disorders (CeTREAD), Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati and by the Veterans Affairs Medical Center, Cincinnati, OH.}

^{The statements in this publication do not necessarily reflect the views or opinions of the Department of Veterans Affairs, the United States Government, or Opiate Addiction Recovery Services.}

The idea that bipolar disorder somehow links with creativity, intelligence, and even genius has an inescapable appeal and is a concept that has kicked around for at least a few decades. It seems somehow heartening to think that at least one psychiatric illness could have a bright side, that some people could productively harness a touch of mania to create notable works of art or literature. Psychologist and bipolar-disorder patient Kay Redfield Jamison published Touched With Fire in 1989, a book-length exploration of “manic depressive illness and the artistic temperament.”

Courtesy Wikipedia/public domain

The problem with looking anecdotally at the past lives of famous creators is that retrospective assessment of psychopathology introduces selection bias and lacks reliability. To get a better handle on the academic background of people who develop bipolar disorder, British psychiatrist Robin M. Murray and his associates ran a study, published last year, that reviewed Swedish national school records during 1988-1997 that included academic-performance assessments for more than 700,000 students at age 16 years. The researchers also examined Swedish hospital-discharge records for psychiatric hospitalizations through the end of 2003, which meant that each of the school kids had an average follow-up of more than 9 years for possible psychiatric hospitalization. During follow-up, 280 of the students had an initial hospitalization for bipolar disorder, and 483 had an initial hospitalization for schizophrenia.

As 16-year-old students, those with an academic assessment that exceeded average by more than two standard deviations had a statistically significant, threefold increased risk for later being diagnosed with bipolar disorder in an adjusted analysis that compared them with all the other students. Students on the low end academically, whose assessment at age 16 years put them more than two standard deviations below average, also had a significantly increased, twofold risk for later being diagnosed with bipolar disorder. In contrast, the risk for a later diagnosis of schizophrenia only increased among students at the low end academically. High academic performance at age 16 linked with protection against later developing schizophrenia.

An intriguing finding, but what does it mean? “Are bipolar genes associated with higher IQ or creativity?” Professor Murray asked after he reviewed this research in a talk earlier this month at the annual congress of the European College of Neuropsychopharmacology. He later told me his skepticism about the bipolar and creativity link, a skepticism that he believes other psychiatrists share. “I don’t think it’s accepted [among most psychiatrists], and I don’t think I accepted it,” he told me in an interview. “You do come across these families [where genius and psychiatric disease coexist]. It hasn’t been accepted, but it’s been there. What is more accepted is that patients with bipolar disorder tend to more often come from middle- and upper-class families than do patients with schizophrenia. You have to take it into account [when you speak with patients with bipolar disorder] that you’re talking with people who are smart, and it may help explain why the genes [predisposing people to develop bipolar disorder] have remained in the population,” Professor Murray ultimately characterized the notion of a creativity and bipolar link as “folklore.”

Whether true or not, the problem with viewing bipolar disorder as possibly having the positive side of conferring on at least some patients a “creative,” muse-like impulse is that I believe it diminishes the real risks that bipolar disorder poses to affected patients and to their friends and family. I spoke recently to a person who had been married to a bipolar patient and heard about the scary, horrific episodes of destructive and self-destructive behavior the illness triggered. The debilitating reality of uncontrolled bipolar disorder makes the hypothesis of a link between bipolar and creativity seem inconsequential.

---Mitchel Zoler (on Twitter @mitchelzoler)

The idea that bipolar disorder somehow links with creativity, intelligence, and even genius has an inescapable appeal and is a concept that has kicked around for at least a few decades. It seems somehow heartening to think that at least one psychiatric illness could have a bright side, that some people could productively harness a touch of mania to create notable works of art or literature. Psychologist and bipolar-disorder patient Kay Redfield Jamison published Touched With Fire in 1989, a book-length exploration of “manic depressive illness and the artistic temperament.”

Courtesy Wikipedia/public domain

The problem with looking anecdotally at the past lives of famous creators is that retrospective assessment of psychopathology introduces selection bias and lacks reliability. To get a better handle on the academic background of people who develop bipolar disorder, British psychiatrist Robin M. Murray and his associates ran a study, published last year, that reviewed Swedish national school records during 1988-1997 that included academic-performance assessments for more than 700,000 students at age 16 years. The researchers also examined Swedish hospital-discharge records for psychiatric hospitalizations through the end of 2003, which meant that each of the school kids had an average follow-up of more than 9 years for possible psychiatric hospitalization. During follow-up, 280 of the students had an initial hospitalization for bipolar disorder, and 483 had an initial hospitalization for schizophrenia.

As 16-year-old students, those with an academic assessment that exceeded average by more than two standard deviations had a statistically significant, threefold increased risk for later being diagnosed with bipolar disorder in an adjusted analysis that compared them with all the other students. Students on the low end academically, whose assessment at age 16 years put them more than two standard deviations below average, also had a significantly increased, twofold risk for later being diagnosed with bipolar disorder. In contrast, the risk for a later diagnosis of schizophrenia only increased among students at the low end academically. High academic performance at age 16 linked with protection against later developing schizophrenia.

An intriguing finding, but what does it mean? “Are bipolar genes associated with higher IQ or creativity?” Professor Murray asked after he reviewed this research in a talk earlier this month at the annual congress of the European College of Neuropsychopharmacology. He later told me his skepticism about the bipolar and creativity link, a skepticism that he believes other psychiatrists share. “I don’t think it’s accepted [among most psychiatrists], and I don’t think I accepted it,” he told me in an interview. “You do come across these families [where genius and psychiatric disease coexist]. It hasn’t been accepted, but it’s been there. What is more accepted is that patients with bipolar disorder tend to more often come from middle- and upper-class families than do patients with schizophrenia. You have to take it into account [when you speak with patients with bipolar disorder] that you’re talking with people who are smart, and it may help explain why the genes [predisposing people to develop bipolar disorder] have remained in the population,” Professor Murray ultimately characterized the notion of a creativity and bipolar link as “folklore.”

Whether true or not, the problem with viewing bipolar disorder as possibly having the positive side of conferring on at least some patients a “creative,” muse-like impulse is that I believe it diminishes the real risks that bipolar disorder poses to affected patients and to their friends and family. I spoke recently to a person who had been married to a bipolar patient and heard about the scary, horrific episodes of destructive and self-destructive behavior the illness triggered. The debilitating reality of uncontrolled bipolar disorder makes the hypothesis of a link between bipolar and creativity seem inconsequential.

---Mitchel Zoler (on Twitter @mitchelzoler)

The idea that bipolar disorder somehow links with creativity, intelligence, and even genius has an inescapable appeal and is a concept that has kicked around for at least a few decades. It seems somehow heartening to think that at least one psychiatric illness could have a bright side, that some people could productively harness a touch of mania to create notable works of art or literature. Psychologist and bipolar-disorder patient Kay Redfield Jamison published Touched With Fire in 1989, a book-length exploration of “manic depressive illness and the artistic temperament.”

Courtesy Wikipedia/public domain

The problem with looking anecdotally at the past lives of famous creators is that retrospective assessment of psychopathology introduces selection bias and lacks reliability. To get a better handle on the academic background of people who develop bipolar disorder, British psychiatrist Robin M. Murray and his associates ran a study, published last year, that reviewed Swedish national school records during 1988-1997 that included academic-performance assessments for more than 700,000 students at age 16 years. The researchers also examined Swedish hospital-discharge records for psychiatric hospitalizations through the end of 2003, which meant that each of the school kids had an average follow-up of more than 9 years for possible psychiatric hospitalization. During follow-up, 280 of the students had an initial hospitalization for bipolar disorder, and 483 had an initial hospitalization for schizophrenia.

As 16-year-old students, those with an academic assessment that exceeded average by more than two standard deviations had a statistically significant, threefold increased risk for later being diagnosed with bipolar disorder in an adjusted analysis that compared them with all the other students. Students on the low end academically, whose assessment at age 16 years put them more than two standard deviations below average, also had a significantly increased, twofold risk for later being diagnosed with bipolar disorder. In contrast, the risk for a later diagnosis of schizophrenia only increased among students at the low end academically. High academic performance at age 16 linked with protection against later developing schizophrenia.

An intriguing finding, but what does it mean? “Are bipolar genes associated with higher IQ or creativity?” Professor Murray asked after he reviewed this research in a talk earlier this month at the annual congress of the European College of Neuropsychopharmacology. He later told me his skepticism about the bipolar and creativity link, a skepticism that he believes other psychiatrists share. “I don’t think it’s accepted [among most psychiatrists], and I don’t think I accepted it,” he told me in an interview. “You do come across these families [where genius and psychiatric disease coexist]. It hasn’t been accepted, but it’s been there. What is more accepted is that patients with bipolar disorder tend to more often come from middle- and upper-class families than do patients with schizophrenia. You have to take it into account [when you speak with patients with bipolar disorder] that you’re talking with people who are smart, and it may help explain why the genes [predisposing people to develop bipolar disorder] have remained in the population,” Professor Murray ultimately characterized the notion of a creativity and bipolar link as “folklore.”

Whether true or not, the problem with viewing bipolar disorder as possibly having the positive side of conferring on at least some patients a “creative,” muse-like impulse is that I believe it diminishes the real risks that bipolar disorder poses to affected patients and to their friends and family. I spoke recently to a person who had been married to a bipolar patient and heard about the scary, horrific episodes of destructive and self-destructive behavior the illness triggered. The debilitating reality of uncontrolled bipolar disorder makes the hypothesis of a link between bipolar and creativity seem inconsequential.

---Mitchel Zoler (on Twitter @mitchelzoler)

CHICAGO – Schizophrenia, bipolar disorder, and major depressive disorder all benefit from early diagnosis and aggressive therapy, and the new First Contact program at Northwestern Memorial Hospital is an attempt to provide it to all three disorders in an orderly way.

"A seamless integration of patient care from the very beginning" is how it was described by Dr. Will Cronenwett, medical director of outpatient psychiatry at Northwestern Memorial Hospital’s Stone Institute of Psychiatry in Chicago. Dr. Cronenwett outlined First Contact in a hospital seminar titled "Reinventing Inpatient Psychiatry."

In the conventional model of care, the prodromes of schizophrenia, bipolar disorder, or depression were each seen as a precursor to that particular illness. Patients were recruited based on the risk of the illness, and treatment and disease progression were studied in that light, according to Dr. Cronenwett’s presentation.

The First Contact model, by contrast, is a clinical staging model dependent on time, and not on predicted illness, said Dr. Cronenwett.

"It’s dependent on somebody’s index presentation. ... Either they’ve identified themselves ... or somebody else has talked to them about getting help," he said. Prospective patients may appear healthy because the program intends to get them as early as possible in the course of the illness, ideally within a year of disease onset.

"Our point is to look at this as a staging model, as opposed to a model where we understand specifically where people are headed," said Dr. Cronenwett.

The First Contact program has three dimensions: clinical, research, and outreach. The treatment goals are symptom relief; education and empowerment; and support for role functioning. A specialized early intervention program is core to First Contact, as are coordinated inpatient and outpatient services. The treatment team will be multidisciplinary and will include community outreach. Cognitive behavioral therapy will be incorporated because it is considered effective for mood symptoms and psychosis in early phases of illness (J. Clin. Psychiatry 2009;70:1206-12). The program’s goals include improving the patient’s adaptation to the illness and increasing their subjective quality of life. Self-management will therefore be stressed, as will cognitive enhancement therapy.

The patient, family, and caregiver will all be educated in the program’s goals.

Research will also be integrated into the First Contact program, seeking disease markers via imaging, genetics, and cognitive changes. Outreach will be used to increase public awareness, promote early self-detection, and encourage early referrals. Dr. Cronenwett said there is evidence, although inconclusive, that early therapy reduces the duration of untreated illness (Acta Psychiatr. Scand. 2008;117:440-8).

Ultimately, Northwestern hopes to create and share guidelines for treatment of these illnesses.

None of this will be easy. In the initial phases, all of these illnesses are difficult to identify with accuracy. The first diagnoses, before the disease prodrome, are often unstable, especially for psychosis, but also for bipolar disease.

"Most people identified as prodromal don’t end up converting to psychosis," said Dr. Cronenwett (Am. J. Psychiatry 2011;168:800-5).

In this particular study, only 35% converted to psychosis, whereas 24% remitted completely. Other diagnoses – including anxiety disorder, depression, mania, and substance use disorder – also remitted over time.

He went on to say that the schizophrenia prodrome is a complicated clinical picture, and that the initial presentation does not predict the outcome. "Schizophrenia prodrome has been the most studied phenomenon to date," he said. "Oftentimes the first symptomatic presentation for what later gets diagnosed as schizophrenia is depression."

The bipolar prodrome, with its age of onset at 0-6 years, can present with any number of characteristics, including "stubborn" and "overly sensitive."

"The bipolar prodrome is probably more confusing than schizophrenia," said Dr. Cronenwett. The most common clinical elements are depressed or elevated mood, anger, perceptual changes, energy changes, functional impairment (Bipolar Disord. 2008;10:555-65). He said it may be 10 years between presenting symptoms and final diagnosis . Major depressive disorder is the least-studied prodrome, and overlaps with other prodromal phenomena, he said.

Dr. Cronenwett disclosed research support from Novartis and from Sunovion Pharmaceuticals.

CHICAGO – Schizophrenia, bipolar disorder, and major depressive disorder all benefit from early diagnosis and aggressive therapy, and the new First Contact program at Northwestern Memorial Hospital is an attempt to provide it to all three disorders in an orderly way.

"A seamless integration of patient care from the very beginning" is how it was described by Dr. Will Cronenwett, medical director of outpatient psychiatry at Northwestern Memorial Hospital’s Stone Institute of Psychiatry in Chicago. Dr. Cronenwett outlined First Contact in a hospital seminar titled "Reinventing Inpatient Psychiatry."

In the conventional model of care, the prodromes of schizophrenia, bipolar disorder, or depression were each seen as a precursor to that particular illness. Patients were recruited based on the risk of the illness, and treatment and disease progression were studied in that light, according to Dr. Cronenwett’s presentation.

The First Contact model, by contrast, is a clinical staging model dependent on time, and not on predicted illness, said Dr. Cronenwett.

"It’s dependent on somebody’s index presentation. ... Either they’ve identified themselves ... or somebody else has talked to them about getting help," he said. Prospective patients may appear healthy because the program intends to get them as early as possible in the course of the illness, ideally within a year of disease onset.

"Our point is to look at this as a staging model, as opposed to a model where we understand specifically where people are headed," said Dr. Cronenwett.

The First Contact program has three dimensions: clinical, research, and outreach. The treatment goals are symptom relief; education and empowerment; and support for role functioning. A specialized early intervention program is core to First Contact, as are coordinated inpatient and outpatient services. The treatment team will be multidisciplinary and will include community outreach. Cognitive behavioral therapy will be incorporated because it is considered effective for mood symptoms and psychosis in early phases of illness (J. Clin. Psychiatry 2009;70:1206-12). The program’s goals include improving the patient’s adaptation to the illness and increasing their subjective quality of life. Self-management will therefore be stressed, as will cognitive enhancement therapy.

The patient, family, and caregiver will all be educated in the program’s goals.

Research will also be integrated into the First Contact program, seeking disease markers via imaging, genetics, and cognitive changes. Outreach will be used to increase public awareness, promote early self-detection, and encourage early referrals. Dr. Cronenwett said there is evidence, although inconclusive, that early therapy reduces the duration of untreated illness (Acta Psychiatr. Scand. 2008;117:440-8).

Ultimately, Northwestern hopes to create and share guidelines for treatment of these illnesses.

None of this will be easy. In the initial phases, all of these illnesses are difficult to identify with accuracy. The first diagnoses, before the disease prodrome, are often unstable, especially for psychosis, but also for bipolar disease.

"Most people identified as prodromal don’t end up converting to psychosis," said Dr. Cronenwett (Am. J. Psychiatry 2011;168:800-5).

In this particular study, only 35% converted to psychosis, whereas 24% remitted completely. Other diagnoses – including anxiety disorder, depression, mania, and substance use disorder – also remitted over time.

He went on to say that the schizophrenia prodrome is a complicated clinical picture, and that the initial presentation does not predict the outcome. "Schizophrenia prodrome has been the most studied phenomenon to date," he said. "Oftentimes the first symptomatic presentation for what later gets diagnosed as schizophrenia is depression."

The bipolar prodrome, with its age of onset at 0-6 years, can present with any number of characteristics, including "stubborn" and "overly sensitive."

"The bipolar prodrome is probably more confusing than schizophrenia," said Dr. Cronenwett. The most common clinical elements are depressed or elevated mood, anger, perceptual changes, energy changes, functional impairment (Bipolar Disord. 2008;10:555-65). He said it may be 10 years between presenting symptoms and final diagnosis . Major depressive disorder is the least-studied prodrome, and overlaps with other prodromal phenomena, he said.

Dr. Cronenwett disclosed research support from Novartis and from Sunovion Pharmaceuticals.

CHICAGO – Schizophrenia, bipolar disorder, and major depressive disorder all benefit from early diagnosis and aggressive therapy, and the new First Contact program at Northwestern Memorial Hospital is an attempt to provide it to all three disorders in an orderly way.

"A seamless integration of patient care from the very beginning" is how it was described by Dr. Will Cronenwett, medical director of outpatient psychiatry at Northwestern Memorial Hospital’s Stone Institute of Psychiatry in Chicago. Dr. Cronenwett outlined First Contact in a hospital seminar titled "Reinventing Inpatient Psychiatry."

In the conventional model of care, the prodromes of schizophrenia, bipolar disorder, or depression were each seen as a precursor to that particular illness. Patients were recruited based on the risk of the illness, and treatment and disease progression were studied in that light, according to Dr. Cronenwett’s presentation.

The First Contact model, by contrast, is a clinical staging model dependent on time, and not on predicted illness, said Dr. Cronenwett.

"It’s dependent on somebody’s index presentation. ... Either they’ve identified themselves ... or somebody else has talked to them about getting help," he said. Prospective patients may appear healthy because the program intends to get them as early as possible in the course of the illness, ideally within a year of disease onset.

"Our point is to look at this as a staging model, as opposed to a model where we understand specifically where people are headed," said Dr. Cronenwett.

The First Contact program has three dimensions: clinical, research, and outreach. The treatment goals are symptom relief; education and empowerment; and support for role functioning. A specialized early intervention program is core to First Contact, as are coordinated inpatient and outpatient services. The treatment team will be multidisciplinary and will include community outreach. Cognitive behavioral therapy will be incorporated because it is considered effective for mood symptoms and psychosis in early phases of illness (J. Clin. Psychiatry 2009;70:1206-12). The program’s goals include improving the patient’s adaptation to the illness and increasing their subjective quality of life. Self-management will therefore be stressed, as will cognitive enhancement therapy.

The patient, family, and caregiver will all be educated in the program’s goals.

Research will also be integrated into the First Contact program, seeking disease markers via imaging, genetics, and cognitive changes. Outreach will be used to increase public awareness, promote early self-detection, and encourage early referrals. Dr. Cronenwett said there is evidence, although inconclusive, that early therapy reduces the duration of untreated illness (Acta Psychiatr. Scand. 2008;117:440-8).

Ultimately, Northwestern hopes to create and share guidelines for treatment of these illnesses.

None of this will be easy. In the initial phases, all of these illnesses are difficult to identify with accuracy. The first diagnoses, before the disease prodrome, are often unstable, especially for psychosis, but also for bipolar disease.

"Most people identified as prodromal don’t end up converting to psychosis," said Dr. Cronenwett (Am. J. Psychiatry 2011;168:800-5).

In this particular study, only 35% converted to psychosis, whereas 24% remitted completely. Other diagnoses – including anxiety disorder, depression, mania, and substance use disorder – also remitted over time.

He went on to say that the schizophrenia prodrome is a complicated clinical picture, and that the initial presentation does not predict the outcome. "Schizophrenia prodrome has been the most studied phenomenon to date," he said. "Oftentimes the first symptomatic presentation for what later gets diagnosed as schizophrenia is depression."

The bipolar prodrome, with its age of onset at 0-6 years, can present with any number of characteristics, including "stubborn" and "overly sensitive."

"The bipolar prodrome is probably more confusing than schizophrenia," said Dr. Cronenwett. The most common clinical elements are depressed or elevated mood, anger, perceptual changes, energy changes, functional impairment (Bipolar Disord. 2008;10:555-65). He said it may be 10 years between presenting symptoms and final diagnosis . Major depressive disorder is the least-studied prodrome, and overlaps with other prodromal phenomena, he said.

Dr. Cronenwett disclosed research support from Novartis and from Sunovion Pharmaceuticals.

PARIS – Recently reported evidence implicating inflammatory mediators in the pathophysiology of bipolar disorder and major depression have opened the door to testing new agents for treating these psychiatric disorders or slowing their progression.

"Bipolar disorder is associated with neuroprogression, and oxidative stress, neurotrophins, and inflammation may underpin this process, Dr. Michael Berk said at the annual Congress of the European College of Neuropsychopharmacology. "Early interventions can potentially improve the outcome" of bipolar disorder, and the new findings give new opportunities to find effective neuroprotective agents, said Dr. Berk, professor and chairman of psychiatry at Deakin University in Geelong, Australia.

"We increasingly think there is a systemic biology that underpins" bipolar disorder and potentially other inflammatory diseases. "The brain does not exist in isolation, and we need to understand that pathways similar to those that underpin risks for cardiovascular disorders, stroke, and osteoporosis might also underpin the risk for psychiatric disorders, and that other treatments might be helpful," he said in an interview.

Based on this concept, and supported by suggestive results from epidemiologic studies, Dr. Berk said he and his associates are running a prospective, randomized study assessing a role for aspirin in treating bipolar disorder, and that they are seeking funding for a second study to test combined treatment with a statin and aspirin in bipolar disorder patients.

"We are only starting to understand the core elements of neuroprogression" in bipolar disorder patients, including the roles of neurogenesis, apoptosis, oxidative stress, and mitochondrial energy generation. "If we accept that these are determining long-term outcomes, it gives us a diversity of novel treatments we can begin to look at that might have a potential impact on these underlying processes. I think this is one of the most hopeful areas of psychiatry."

Evidence of a role for inflammation in bipolar disorder and major depression includes the finding by Dr. Berk and his associates that women who received statin treatment had about a 2% incidence of newly diagnosed major depressive disorder during 10 years of follow-up, significantly less than the 10% incidence rate among women who did not receive a statin, in a nonrandomized study that controlled for age (Psychother. Psychosom. 2010;79:323-5).

In another study, Dr. Berk and his associates found a link between elevated serum levels of high sensitivity C-reactive protein (hsCRP) and the incidence of major depressive disorder. They followed 644 randomly selected women aged 20-84 and with no history of depression at baseline for 10 years. During follow-up, the rate of new-onset major depressive disorder rose by a statistically significant 44% for each one standard deviation increase in the log-transformed level of serum hsCRP, after adjustment for baseline differences in weight, smoking history, and use of nonsteroidal anti-inflammatory drugs (Br. J. Psychiatry 2010;197:372-7).

Also, a 2006 report from Irish researchers had results from a study of the plasma levels of five different cytokines in 42 people aged 1-68, including nine with bipolar affective disorder in the depressive phase, 12 with bipolar affective disorder in the manic phase, and 21 control people with no personal or family history of a mood disorder. The results showed significantly elevated plasma levels of interleukin-8 and tumor necrosis factor-α in both subgroups of bipolar disorder patients studied compared with the controls (J. Affective Disorders 2006;90:263-7).

Dr. Berk also reported as yet unpublished results from his group that further supported a possible causal role for inflammation or autoimmunity in major depression. Results from one study showed significantly lower plasma levels of tumor necrosis factor-α in control subjects, compared with patients with melancholia or recurrent major depressive disorder. Results from a second study showed a significantly higher level of IgM that reacted against an oxidatively modified form of tryptophan in patients with new-onset major depressive disorder. "This may be a major cause of neuroprogression and a factor in chronicity and treatment resistance," he said.

In addition, recent findings on the trajectory of major depression and bipolar disorder also suggest a critical role for early treatment. Although Dr. Berk cautioned that "we need prospective data, and we need to be cautious in interpreting the data" now available, recent findings suggest that "the earlier on in illness the simpler treatment can be and the more likely is response to treatment," he said. Conversely, more advanced bipolar disorder appears to be more treatment resistant and only treatable with more complex regimens. The basis for these associations seems to be the progressive neuropathologic processes that underlie these disorders. "Mania appears to be the most neurotoxic phase of [bipolar disorder] illness," he said. "Prevention of mania may be most effective for preventing neuroprogression."

He cited clinical suggestions of progression to more treatment-resistant forms of disease. "You often see the history that initial treatment with antidepressant drugs helped, but later they did not." For example, in a recent meta-analysis of 12 treatment studies involving more than 4,000 total patients with bipolar disorder, Dr. Berk and his associates found patients in the earliest stages of their disease consistently had better responses to treatment, compared with patients who had experienced more episodes of mania or depression. "Vigorous attention needs to be paid to early diagnosis," they wrote in their report published earlier this year (Bipolar Dis. 2011;13:87-98). "There is every possibility that early and appropriate treatment and the prevention of new episodes may prevent this cascade," they wrote, but also added "this remains to be established."

Dr. Berk said he had been a speaker for, a consultant to, and has received research grants from Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Servier; he has been a speaker for and consultant to AstraZeneca, Janssen Cilag, and Lundbeck; he has been a speaker for Merck, Sanofi Synthélabo, and Solvay and Wyeth, and he has received research grants from Organon, Novartis, and Mayne.

PARIS – Recently reported evidence implicating inflammatory mediators in the pathophysiology of bipolar disorder and major depression have opened the door to testing new agents for treating these psychiatric disorders or slowing their progression.

"Bipolar disorder is associated with neuroprogression, and oxidative stress, neurotrophins, and inflammation may underpin this process, Dr. Michael Berk said at the annual Congress of the European College of Neuropsychopharmacology. "Early interventions can potentially improve the outcome" of bipolar disorder, and the new findings give new opportunities to find effective neuroprotective agents, said Dr. Berk, professor and chairman of psychiatry at Deakin University in Geelong, Australia.

"We increasingly think there is a systemic biology that underpins" bipolar disorder and potentially other inflammatory diseases. "The brain does not exist in isolation, and we need to understand that pathways similar to those that underpin risks for cardiovascular disorders, stroke, and osteoporosis might also underpin the risk for psychiatric disorders, and that other treatments might be helpful," he said in an interview.

Based on this concept, and supported by suggestive results from epidemiologic studies, Dr. Berk said he and his associates are running a prospective, randomized study assessing a role for aspirin in treating bipolar disorder, and that they are seeking funding for a second study to test combined treatment with a statin and aspirin in bipolar disorder patients.

"We are only starting to understand the core elements of neuroprogression" in bipolar disorder patients, including the roles of neurogenesis, apoptosis, oxidative stress, and mitochondrial energy generation. "If we accept that these are determining long-term outcomes, it gives us a diversity of novel treatments we can begin to look at that might have a potential impact on these underlying processes. I think this is one of the most hopeful areas of psychiatry."

Evidence of a role for inflammation in bipolar disorder and major depression includes the finding by Dr. Berk and his associates that women who received statin treatment had about a 2% incidence of newly diagnosed major depressive disorder during 10 years of follow-up, significantly less than the 10% incidence rate among women who did not receive a statin, in a nonrandomized study that controlled for age (Psychother. Psychosom. 2010;79:323-5).

In another study, Dr. Berk and his associates found a link between elevated serum levels of high sensitivity C-reactive protein (hsCRP) and the incidence of major depressive disorder. They followed 644 randomly selected women aged 20-84 and with no history of depression at baseline for 10 years. During follow-up, the rate of new-onset major depressive disorder rose by a statistically significant 44% for each one standard deviation increase in the log-transformed level of serum hsCRP, after adjustment for baseline differences in weight, smoking history, and use of nonsteroidal anti-inflammatory drugs (Br. J. Psychiatry 2010;197:372-7).

Also, a 2006 report from Irish researchers had results from a study of the plasma levels of five different cytokines in 42 people aged 1-68, including nine with bipolar affective disorder in the depressive phase, 12 with bipolar affective disorder in the manic phase, and 21 control people with no personal or family history of a mood disorder. The results showed significantly elevated plasma levels of interleukin-8 and tumor necrosis factor-α in both subgroups of bipolar disorder patients studied compared with the controls (J. Affective Disorders 2006;90:263-7).

Dr. Berk also reported as yet unpublished results from his group that further supported a possible causal role for inflammation or autoimmunity in major depression. Results from one study showed significantly lower plasma levels of tumor necrosis factor-α in control subjects, compared with patients with melancholia or recurrent major depressive disorder. Results from a second study showed a significantly higher level of IgM that reacted against an oxidatively modified form of tryptophan in patients with new-onset major depressive disorder. "This may be a major cause of neuroprogression and a factor in chronicity and treatment resistance," he said.

In addition, recent findings on the trajectory of major depression and bipolar disorder also suggest a critical role for early treatment. Although Dr. Berk cautioned that "we need prospective data, and we need to be cautious in interpreting the data" now available, recent findings suggest that "the earlier on in illness the simpler treatment can be and the more likely is response to treatment," he said. Conversely, more advanced bipolar disorder appears to be more treatment resistant and only treatable with more complex regimens. The basis for these associations seems to be the progressive neuropathologic processes that underlie these disorders. "Mania appears to be the most neurotoxic phase of [bipolar disorder] illness," he said. "Prevention of mania may be most effective for preventing neuroprogression."

He cited clinical suggestions of progression to more treatment-resistant forms of disease. "You often see the history that initial treatment with antidepressant drugs helped, but later they did not." For example, in a recent meta-analysis of 12 treatment studies involving more than 4,000 total patients with bipolar disorder, Dr. Berk and his associates found patients in the earliest stages of their disease consistently had better responses to treatment, compared with patients who had experienced more episodes of mania or depression. "Vigorous attention needs to be paid to early diagnosis," they wrote in their report published earlier this year (Bipolar Dis. 2011;13:87-98). "There is every possibility that early and appropriate treatment and the prevention of new episodes may prevent this cascade," they wrote, but also added "this remains to be established."

Dr. Berk said he had been a speaker for, a consultant to, and has received research grants from Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Servier; he has been a speaker for and consultant to AstraZeneca, Janssen Cilag, and Lundbeck; he has been a speaker for Merck, Sanofi Synthélabo, and Solvay and Wyeth, and he has received research grants from Organon, Novartis, and Mayne.

PARIS – Recently reported evidence implicating inflammatory mediators in the pathophysiology of bipolar disorder and major depression have opened the door to testing new agents for treating these psychiatric disorders or slowing their progression.

"Bipolar disorder is associated with neuroprogression, and oxidative stress, neurotrophins, and inflammation may underpin this process, Dr. Michael Berk said at the annual Congress of the European College of Neuropsychopharmacology. "Early interventions can potentially improve the outcome" of bipolar disorder, and the new findings give new opportunities to find effective neuroprotective agents, said Dr. Berk, professor and chairman of psychiatry at Deakin University in Geelong, Australia.

"We increasingly think there is a systemic biology that underpins" bipolar disorder and potentially other inflammatory diseases. "The brain does not exist in isolation, and we need to understand that pathways similar to those that underpin risks for cardiovascular disorders, stroke, and osteoporosis might also underpin the risk for psychiatric disorders, and that other treatments might be helpful," he said in an interview.

Based on this concept, and supported by suggestive results from epidemiologic studies, Dr. Berk said he and his associates are running a prospective, randomized study assessing a role for aspirin in treating bipolar disorder, and that they are seeking funding for a second study to test combined treatment with a statin and aspirin in bipolar disorder patients.

"We are only starting to understand the core elements of neuroprogression" in bipolar disorder patients, including the roles of neurogenesis, apoptosis, oxidative stress, and mitochondrial energy generation. "If we accept that these are determining long-term outcomes, it gives us a diversity of novel treatments we can begin to look at that might have a potential impact on these underlying processes. I think this is one of the most hopeful areas of psychiatry."

Evidence of a role for inflammation in bipolar disorder and major depression includes the finding by Dr. Berk and his associates that women who received statin treatment had about a 2% incidence of newly diagnosed major depressive disorder during 10 years of follow-up, significantly less than the 10% incidence rate among women who did not receive a statin, in a nonrandomized study that controlled for age (Psychother. Psychosom. 2010;79:323-5).

In another study, Dr. Berk and his associates found a link between elevated serum levels of high sensitivity C-reactive protein (hsCRP) and the incidence of major depressive disorder. They followed 644 randomly selected women aged 20-84 and with no history of depression at baseline for 10 years. During follow-up, the rate of new-onset major depressive disorder rose by a statistically significant 44% for each one standard deviation increase in the log-transformed level of serum hsCRP, after adjustment for baseline differences in weight, smoking history, and use of nonsteroidal anti-inflammatory drugs (Br. J. Psychiatry 2010;197:372-7).

Also, a 2006 report from Irish researchers had results from a study of the plasma levels of five different cytokines in 42 people aged 1-68, including nine with bipolar affective disorder in the depressive phase, 12 with bipolar affective disorder in the manic phase, and 21 control people with no personal or family history of a mood disorder. The results showed significantly elevated plasma levels of interleukin-8 and tumor necrosis factor-α in both subgroups of bipolar disorder patients studied compared with the controls (J. Affective Disorders 2006;90:263-7).

Dr. Berk also reported as yet unpublished results from his group that further supported a possible causal role for inflammation or autoimmunity in major depression. Results from one study showed significantly lower plasma levels of tumor necrosis factor-α in control subjects, compared with patients with melancholia or recurrent major depressive disorder. Results from a second study showed a significantly higher level of IgM that reacted against an oxidatively modified form of tryptophan in patients with new-onset major depressive disorder. "This may be a major cause of neuroprogression and a factor in chronicity and treatment resistance," he said.

In addition, recent findings on the trajectory of major depression and bipolar disorder also suggest a critical role for early treatment. Although Dr. Berk cautioned that "we need prospective data, and we need to be cautious in interpreting the data" now available, recent findings suggest that "the earlier on in illness the simpler treatment can be and the more likely is response to treatment," he said. Conversely, more advanced bipolar disorder appears to be more treatment resistant and only treatable with more complex regimens. The basis for these associations seems to be the progressive neuropathologic processes that underlie these disorders. "Mania appears to be the most neurotoxic phase of [bipolar disorder] illness," he said. "Prevention of mania may be most effective for preventing neuroprogression."

He cited clinical suggestions of progression to more treatment-resistant forms of disease. "You often see the history that initial treatment with antidepressant drugs helped, but later they did not." For example, in a recent meta-analysis of 12 treatment studies involving more than 4,000 total patients with bipolar disorder, Dr. Berk and his associates found patients in the earliest stages of their disease consistently had better responses to treatment, compared with patients who had experienced more episodes of mania or depression. "Vigorous attention needs to be paid to early diagnosis," they wrote in their report published earlier this year (Bipolar Dis. 2011;13:87-98). "There is every possibility that early and appropriate treatment and the prevention of new episodes may prevent this cascade," they wrote, but also added "this remains to be established."

Dr. Berk said he had been a speaker for, a consultant to, and has received research grants from Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Servier; he has been a speaker for and consultant to AstraZeneca, Janssen Cilag, and Lundbeck; he has been a speaker for Merck, Sanofi Synthélabo, and Solvay and Wyeth, and he has received research grants from Organon, Novartis, and Mayne.

PARIS – A 21-week program of "functional remediation" for 220 adults with bipolar disorder was more effective than psychosocial education or usual treatment in improving psychosocial functioning at 6 months of follow-up.

The multicenter trial randomized euthymic adults with bipolar disorder type I or II at 10 centers in Spain to 21 weeks of treatment in one of three groups: weekly 90-minute group sessions for functional remediation; group psychoeducation sessions, or a control group that got treatment as usual. The functional remediation sessions covered aspects of cognition and psychosocial restoration, Dr. Eduard Vieta said at the annual congress of the European College of Neuropsychopharmacology.

The study measured functional status using the Functional Assessment Short Test (FAST). The FAST provides on objective measure, compared with assessments of quality of life that produce subjective results, said Dr. Vieta, director of the Bipolar Disorders Program at the Clinical Institute of Neuroscience, University of Barcelona. To be eligible for the study, patients had to have FAST scores of 18 or greater, which allowed room to show improvement, and only patients up to age 50 years were accepted in order to avoid cognitive deficits associated with older age.

Previous data using FAST show that patients with bipolar disorder have significantly lower functioning in measures of autonomy, cognition, financial issues, interpersonal functioning, leisure time, and overall scores compared with people without bipolar disorder (Bipolar Disord. 2009;11:401-9). In one study, cognitive function scores on the FAST at baseline predicted functional outcome 4 years later (J. Affect. Disord. 2010;121:156-60).

In the current study, there were no significant differences at baseline in functioning between groups as measured by FAST scores. In the functional remediation group, 30% discontinued treatment during the study compared with 27% in the psychoeducation group and 18% getting treatment as usual.

At 6-month follow-up, FAST scores of functioning were significantly better in the functional remediation group compared with the psychoeducation group or the control group. A preliminary analysis of results suggests that the difference in FAST scores was significant to a P value of .001, reported Dr. Vieta and his associate in the study, Carla Torrent, Ph.D., also with both of the University of Barcelona.

In an assessment of effect size, the functional remediation had a large effect, the psychoeducation had a small effect, and treatment as usual had essentially no effect, he said.

Among the various functional domains, functional remediation had the most impact on cognitive, interpersonal, and autonomy domains, each with a medium effect. Small effects were seen on leisure, financial, and occupational domains.

The functional remediation program addressed cognition and psychosocial restoration using neurocognitive techniques for daily life. It included education about cognitive deficits and their impact on daily life, and sought to increase insight regrading cognitive dysfunctions. The program provided patients with strategies to manage cognitive deficits, primarily in the areas of attention, memory, and executive function. In some cases, the patient’s family participated to help the patient practice the strategies and to reinforce the learning.

The neurocognitive behavioral approach in the program employed modeling techniques, role playing, verbal instructions, self-instructions, positive reinforcement, and metacognitive cues.

Each 90-minute session began with a 15-minute discussion of assigned homework and a 5-minute warm-up task, followed by 20 minutes of theory and cognitive strategies. Practical exercises for the next 45 minutes were followed by 5 minutes to focus on take-home points and tasks to do at home.

The 21 sessions focused on specific topics grouped within categories of education, attention, memory, executive functions, and improving communication, autonomy, and stress management. Sessions 12-16, for example, focused on executive functions, with sessions on self-instructions and self-monitoring of executive functions, programming and organizing activities, establishing priorities and time management, problem-solving techniques, and solving problems.

The investigators have not yet done a cost-benefit analysis, but a functional remediation program should not be too expensive, Dr. Vieta said. "You just need one neuropsychologist" or two to organize and lead the program, he said. Previous cost analyses have shown group psychoeducation to be cost effective. "This should be, too," he said.

Medication can treat acute episodes of bipolar disorder, and help prevent relapse and recurrences. Group psychoeducation is effective in reducing recurrences in euthymic bipolar patients, but it does not tackle cognitive impairment or functioning. Impaired cognition has been associated with nonadherence to therapy.

Previous studies suggest that impaired functioning remains in many patients even after successful treatment for bipolar disorder. In one study, conventional treatment produced syndromal recovery in 85% at 6 months and 98% at 2 years, but functional recovery was seen in only 30% at 6 months and 38% at 2 years (Am. J. Psychiatry 2000;157:220-8).

The ideal combination of treatments for bipolar disorder may be a combination of medication, patient and family psychoeducation, training in healthy habits, and functional remediation, he suggested.

Dr. Vieta disclosed financial relationships with several institutions , including Almirall, Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Novartis, Otsuka, Pfizer, Richter, Sanofi-Aventis, the SENY Foundation,, Lundbeck, MSD, Takeda, UBC, Forest Research Institute, Jazz, Pierre-Fabre, Solvay, the Stanley Medical Research Institute, and the Spanish Ministry of Science and Education.

PARIS – A 21-week program of "functional remediation" for 220 adults with bipolar disorder was more effective than psychosocial education or usual treatment in improving psychosocial functioning at 6 months of follow-up.

The multicenter trial randomized euthymic adults with bipolar disorder type I or II at 10 centers in Spain to 21 weeks of treatment in one of three groups: weekly 90-minute group sessions for functional remediation; group psychoeducation sessions, or a control group that got treatment as usual. The functional remediation sessions covered aspects of cognition and psychosocial restoration, Dr. Eduard Vieta said at the annual congress of the European College of Neuropsychopharmacology.

The study measured functional status using the Functional Assessment Short Test (FAST). The FAST provides on objective measure, compared with assessments of quality of life that produce subjective results, said Dr. Vieta, director of the Bipolar Disorders Program at the Clinical Institute of Neuroscience, University of Barcelona. To be eligible for the study, patients had to have FAST scores of 18 or greater, which allowed room to show improvement, and only patients up to age 50 years were accepted in order to avoid cognitive deficits associated with older age.

Previous data using FAST show that patients with bipolar disorder have significantly lower functioning in measures of autonomy, cognition, financial issues, interpersonal functioning, leisure time, and overall scores compared with people without bipolar disorder (Bipolar Disord. 2009;11:401-9). In one study, cognitive function scores on the FAST at baseline predicted functional outcome 4 years later (J. Affect. Disord. 2010;121:156-60).

In the current study, there were no significant differences at baseline in functioning between groups as measured by FAST scores. In the functional remediation group, 30% discontinued treatment during the study compared with 27% in the psychoeducation group and 18% getting treatment as usual.

At 6-month follow-up, FAST scores of functioning were significantly better in the functional remediation group compared with the psychoeducation group or the control group. A preliminary analysis of results suggests that the difference in FAST scores was significant to a P value of .001, reported Dr. Vieta and his associate in the study, Carla Torrent, Ph.D., also with both of the University of Barcelona.

In an assessment of effect size, the functional remediation had a large effect, the psychoeducation had a small effect, and treatment as usual had essentially no effect, he said.

Among the various functional domains, functional remediation had the most impact on cognitive, interpersonal, and autonomy domains, each with a medium effect. Small effects were seen on leisure, financial, and occupational domains.

The functional remediation program addressed cognition and psychosocial restoration using neurocognitive techniques for daily life. It included education about cognitive deficits and their impact on daily life, and sought to increase insight regrading cognitive dysfunctions. The program provided patients with strategies to manage cognitive deficits, primarily in the areas of attention, memory, and executive function. In some cases, the patient’s family participated to help the patient practice the strategies and to reinforce the learning.

The neurocognitive behavioral approach in the program employed modeling techniques, role playing, verbal instructions, self-instructions, positive reinforcement, and metacognitive cues.

Each 90-minute session began with a 15-minute discussion of assigned homework and a 5-minute warm-up task, followed by 20 minutes of theory and cognitive strategies. Practical exercises for the next 45 minutes were followed by 5 minutes to focus on take-home points and tasks to do at home.

The 21 sessions focused on specific topics grouped within categories of education, attention, memory, executive functions, and improving communication, autonomy, and stress management. Sessions 12-16, for example, focused on executive functions, with sessions on self-instructions and self-monitoring of executive functions, programming and organizing activities, establishing priorities and time management, problem-solving techniques, and solving problems.

The investigators have not yet done a cost-benefit analysis, but a functional remediation program should not be too expensive, Dr. Vieta said. "You just need one neuropsychologist" or two to organize and lead the program, he said. Previous cost analyses have shown group psychoeducation to be cost effective. "This should be, too," he said.

Medication can treat acute episodes of bipolar disorder, and help prevent relapse and recurrences. Group psychoeducation is effective in reducing recurrences in euthymic bipolar patients, but it does not tackle cognitive impairment or functioning. Impaired cognition has been associated with nonadherence to therapy.

Previous studies suggest that impaired functioning remains in many patients even after successful treatment for bipolar disorder. In one study, conventional treatment produced syndromal recovery in 85% at 6 months and 98% at 2 years, but functional recovery was seen in only 30% at 6 months and 38% at 2 years (Am. J. Psychiatry 2000;157:220-8).

The ideal combination of treatments for bipolar disorder may be a combination of medication, patient and family psychoeducation, training in healthy habits, and functional remediation, he suggested.

Dr. Vieta disclosed financial relationships with several institutions , including Almirall, Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Novartis, Otsuka, Pfizer, Richter, Sanofi-Aventis, the SENY Foundation,, Lundbeck, MSD, Takeda, UBC, Forest Research Institute, Jazz, Pierre-Fabre, Solvay, the Stanley Medical Research Institute, and the Spanish Ministry of Science and Education.

PARIS – A 21-week program of "functional remediation" for 220 adults with bipolar disorder was more effective than psychosocial education or usual treatment in improving psychosocial functioning at 6 months of follow-up.

The multicenter trial randomized euthymic adults with bipolar disorder type I or II at 10 centers in Spain to 21 weeks of treatment in one of three groups: weekly 90-minute group sessions for functional remediation; group psychoeducation sessions, or a control group that got treatment as usual. The functional remediation sessions covered aspects of cognition and psychosocial restoration, Dr. Eduard Vieta said at the annual congress of the European College of Neuropsychopharmacology.

The study measured functional status using the Functional Assessment Short Test (FAST). The FAST provides on objective measure, compared with assessments of quality of life that produce subjective results, said Dr. Vieta, director of the Bipolar Disorders Program at the Clinical Institute of Neuroscience, University of Barcelona. To be eligible for the study, patients had to have FAST scores of 18 or greater, which allowed room to show improvement, and only patients up to age 50 years were accepted in order to avoid cognitive deficits associated with older age.

Previous data using FAST show that patients with bipolar disorder have significantly lower functioning in measures of autonomy, cognition, financial issues, interpersonal functioning, leisure time, and overall scores compared with people without bipolar disorder (Bipolar Disord. 2009;11:401-9). In one study, cognitive function scores on the FAST at baseline predicted functional outcome 4 years later (J. Affect. Disord. 2010;121:156-60).

In the current study, there were no significant differences at baseline in functioning between groups as measured by FAST scores. In the functional remediation group, 30% discontinued treatment during the study compared with 27% in the psychoeducation group and 18% getting treatment as usual.

At 6-month follow-up, FAST scores of functioning were significantly better in the functional remediation group compared with the psychoeducation group or the control group. A preliminary analysis of results suggests that the difference in FAST scores was significant to a P value of .001, reported Dr. Vieta and his associate in the study, Carla Torrent, Ph.D., also with both of the University of Barcelona.

In an assessment of effect size, the functional remediation had a large effect, the psychoeducation had a small effect, and treatment as usual had essentially no effect, he said.

Among the various functional domains, functional remediation had the most impact on cognitive, interpersonal, and autonomy domains, each with a medium effect. Small effects were seen on leisure, financial, and occupational domains.

The functional remediation program addressed cognition and psychosocial restoration using neurocognitive techniques for daily life. It included education about cognitive deficits and their impact on daily life, and sought to increase insight regrading cognitive dysfunctions. The program provided patients with strategies to manage cognitive deficits, primarily in the areas of attention, memory, and executive function. In some cases, the patient’s family participated to help the patient practice the strategies and to reinforce the learning.

The neurocognitive behavioral approach in the program employed modeling techniques, role playing, verbal instructions, self-instructions, positive reinforcement, and metacognitive cues.

Each 90-minute session began with a 15-minute discussion of assigned homework and a 5-minute warm-up task, followed by 20 minutes of theory and cognitive strategies. Practical exercises for the next 45 minutes were followed by 5 minutes to focus on take-home points and tasks to do at home.

The 21 sessions focused on specific topics grouped within categories of education, attention, memory, executive functions, and improving communication, autonomy, and stress management. Sessions 12-16, for example, focused on executive functions, with sessions on self-instructions and self-monitoring of executive functions, programming and organizing activities, establishing priorities and time management, problem-solving techniques, and solving problems.

The investigators have not yet done a cost-benefit analysis, but a functional remediation program should not be too expensive, Dr. Vieta said. "You just need one neuropsychologist" or two to organize and lead the program, he said. Previous cost analyses have shown group psychoeducation to be cost effective. "This should be, too," he said.

Medication can treat acute episodes of bipolar disorder, and help prevent relapse and recurrences. Group psychoeducation is effective in reducing recurrences in euthymic bipolar patients, but it does not tackle cognitive impairment or functioning. Impaired cognition has been associated with nonadherence to therapy.

Previous studies suggest that impaired functioning remains in many patients even after successful treatment for bipolar disorder. In one study, conventional treatment produced syndromal recovery in 85% at 6 months and 98% at 2 years, but functional recovery was seen in only 30% at 6 months and 38% at 2 years (Am. J. Psychiatry 2000;157:220-8).

The ideal combination of treatments for bipolar disorder may be a combination of medication, patient and family psychoeducation, training in healthy habits, and functional remediation, he suggested.

Dr. Vieta disclosed financial relationships with several institutions , including Almirall, Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Novartis, Otsuka, Pfizer, Richter, Sanofi-Aventis, the SENY Foundation,, Lundbeck, MSD, Takeda, UBC, Forest Research Institute, Jazz, Pierre-Fabre, Solvay, the Stanley Medical Research Institute, and the Spanish Ministry of Science and Education.

PARIS – Many psychiatrists have overdiagnosed bipolar disorder in children and adolescents over the past decade, which has led to overly aggressive treatment with second-generation antipsychotic drugs, Dr. David Cohen said at a press briefing at the annual congress of the European College of Neuropsychopharmacology.

This issue might start to resolve with the scheduled publication in 2013 of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), because the current draft establishes a new diagnostic category that Dr. Cohen said is more appropriate for many of these children: temper dysregulation disorder with dysphoria (TDDD).

(c) Mitchel L. Zoler/IMNG

"I’m very pleased that the DSM 5 Working Group intends to improve the way these kids will be characterized by changing the label to TDDD. I think this labeling will help to better characterize this disease and not confuse [these patients] with bipolar disorder," Dr. Cohen said in an interview. Results from follow-up studies suggest that children and adolescents with the spectrum of symptoms included in TDDD, which could also be labeled today as severe mood dysregulation, "may be risk factors for [the diagnosis of] bipolar disorder in adulthood, in perhaps 20% of patients, but many do not develop bipolar disorder," said Dr. Cohen, professor of psychiatry at the University of Paris and head of the department of child and adolescent psychiatry at La Salpêtrière Hospital in Paris.

"I have [results from] long follow-up studies that do not show that manic symptoms in children lead to bipolar disorder" when they become adults. Certain children with symptoms that often characterize bipolar disorder "may be at risk for having bipolar disorder as adults, but not at high rates. Only after a child is 11 or 12 years old and you see these symptoms can you be confident that it is likely bipolar disorder. Adolescence is when" the diagnosis of bipolar can start to be made with any confidence, he said.

"Puberty is a good threshold for talking about bipolar disorder. TDDD is a better diagnosis for pre-pubertal children" because at that stage of life the manic symptoms of bipolar disease, such as irritability, mood change, hyperactivity, and sleep disturbance, can serve as risk markers for the eventual development of bipolar disease, but not at high rates. "Only once a child is at least 11 or 12 years old can you see these symptoms and be confident that it is likely bipolar disease of adolescence or beyond." Adolescence is when the diagnosis of bipolar disease can truly start. A reliable diagnosis of bipolar disorder in a younger child "is really exceptional."

Dr. Cohen’s views are at odds with recent trends in the diagnosis of bipolar disorder among children in the United States. American psychiatrists have, over the past decade, diagnosed bipolar disorder in children as young as age 5 years, resulting in incidence rates that ballooned by as much as four-fold during the 2000s, according to insurance claims data, commented Dr. Rasin Somer Diler, medical director of the Inpatient Child and Adolescent Bipolar Services program at the University of Pittsbugh. Dr. Diler said that in his own program diagnosis rates in younger children have risen by about a third from the late 1990s through the late 2000s, but he added that this was in a referral program that might differ from what has occurred in U.S. community hospitals and office practices.*

This shift in practice has also led to inordinate prescribing of second-generation antipsychotics to children, Dr. Cohen said. "These drugs are only appropriate for bipolar disorder episodes in adolescents."

Psychiatrists "usually use adult criteria to diagnose bipolar disorder" in children and adolescents. "Manic symptoms can be quite frequent in children, but I don’t label them as having bipolar disorder. With manic episodes and bipolar disorder in children you need to see how the symptoms appear over time. You cannot do a proper differential diagnosis in a few days."

Another issue when diagnosing bipolar disorder in adolescents is the differential diagnosis, distinguishing bipolar disorder from schizophrenia or attention-deficit/hyperactivity disorder (ADHD), conditions that also can present with manic symptoms. "ADHD is much more prevalent in children than bipolar disorder. If you see a child with irritability, it is much more likely to be ADHD." Schizophrenia also poses a diagnostic challenge. "Sometimes, it is only by follow-up of adolescents that makes us confident that the diagnosis is bipolar disorder, compared with schizophrenia."

Adolescents who are accurately diagnosed with bipolar disease will likely require long-term treatment. Dr. Cohen reported his experience with about 60 patients first diagnosed with bipolar disease as adolescents he followed for an average of 8 years. From this group, only five patients did not experience relapses. "When you continue treatment, relapses are fewer and the symptoms remain under better control." But he acknowledged that his experience likely involves a referral bias because his service generally only sees the most severely affected adolescents. He said that he would consider attempting treatment withdrawal from an adolescent patient who has remained mood stabilized on treatment for about 5 years, but he avoids trying treatment withdrawal at times of life with elevated emotional stress, such as when schooling ends or when patients face issues in their sexual relationships.

When bipolar disease is appropriately diagnosed in an adolescent, treatment must be chosen judiciously. Dr. Cohen said he an his associates recently performed a meta-analysis of 41 controlled studies that examined treatment with second-generation antipsychotics in more than 4,000 children and adolescents, including 12 studies that involved youths with bipolar disorder. "Compared with adults, youths were found to be more vulnerable to the adverse effects of second-generation antipsychotics." These adverse effects included somnolence and sedation, weight gain, metabolic changes including prolactin effects, and extrapyramidal motor symptoms. "Tolerability profiles should be considered in making treatment decisions," he said. (see table). Patients who fail to adequately respond to at least two second-generation antipsychotic drugs can be considered candidates for electroconvulsive therapy (ECT).

"In cases of no response to pharmacological treatment, ECT has proven to be safe and effective for both manic and depressive episodes in adolescents with severe illness," Dr. Cohen said. In addition, these patients have generally had favorable reactions to ECT. "Despite negative views about ECT in public opinion, adolescent recipients and their patients share overall positive attitudes toward ECT," he said.

Dr. Cohen said he has received funding from Schering-Plough, Bristol-Myers Squibb. Otsuka, Janssen, Sanofi-Aventis, and Shire.

*9/5/11 -- Dr. Diler's statement and further clarification were added this story.

PARIS – Many psychiatrists have overdiagnosed bipolar disorder in children and adolescents over the past decade, which has led to overly aggressive treatment with second-generation antipsychotic drugs, Dr. David Cohen said at a press briefing at the annual congress of the European College of Neuropsychopharmacology.

This issue might start to resolve with the scheduled publication in 2013 of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), because the current draft establishes a new diagnostic category that Dr. Cohen said is more appropriate for many of these children: temper dysregulation disorder with dysphoria (TDDD).

(c) Mitchel L. Zoler/IMNG

"I’m very pleased that the DSM 5 Working Group intends to improve the way these kids will be characterized by changing the label to TDDD. I think this labeling will help to better characterize this disease and not confuse [these patients] with bipolar disorder," Dr. Cohen said in an interview. Results from follow-up studies suggest that children and adolescents with the spectrum of symptoms included in TDDD, which could also be labeled today as severe mood dysregulation, "may be risk factors for [the diagnosis of] bipolar disorder in adulthood, in perhaps 20% of patients, but many do not develop bipolar disorder," said Dr. Cohen, professor of psychiatry at the University of Paris and head of the department of child and adolescent psychiatry at La Salpêtrière Hospital in Paris.

"I have [results from] long follow-up studies that do not show that manic symptoms in children lead to bipolar disorder" when they become adults. Certain children with symptoms that often characterize bipolar disorder "may be at risk for having bipolar disorder as adults, but not at high rates. Only after a child is 11 or 12 years old and you see these symptoms can you be confident that it is likely bipolar disorder. Adolescence is when" the diagnosis of bipolar can start to be made with any confidence, he said.

"Puberty is a good threshold for talking about bipolar disorder. TDDD is a better diagnosis for pre-pubertal children" because at that stage of life the manic symptoms of bipolar disease, such as irritability, mood change, hyperactivity, and sleep disturbance, can serve as risk markers for the eventual development of bipolar disease, but not at high rates. "Only once a child is at least 11 or 12 years old can you see these symptoms and be confident that it is likely bipolar disease of adolescence or beyond." Adolescence is when the diagnosis of bipolar disease can truly start. A reliable diagnosis of bipolar disorder in a younger child "is really exceptional."

Dr. Cohen’s views are at odds with recent trends in the diagnosis of bipolar disorder among children in the United States. American psychiatrists have, over the past decade, diagnosed bipolar disorder in children as young as age 5 years, resulting in incidence rates that ballooned by as much as four-fold during the 2000s, according to insurance claims data, commented Dr. Rasin Somer Diler, medical director of the Inpatient Child and Adolescent Bipolar Services program at the University of Pittsbugh. Dr. Diler said that in his own program diagnosis rates in younger children have risen by about a third from the late 1990s through the late 2000s, but he added that this was in a referral program that might differ from what has occurred in U.S. community hospitals and office practices.*

This shift in practice has also led to inordinate prescribing of second-generation antipsychotics to children, Dr. Cohen said. "These drugs are only appropriate for bipolar disorder episodes in adolescents."

Psychiatrists "usually use adult criteria to diagnose bipolar disorder" in children and adolescents. "Manic symptoms can be quite frequent in children, but I don’t label them as having bipolar disorder. With manic episodes and bipolar disorder in children you need to see how the symptoms appear over time. You cannot do a proper differential diagnosis in a few days."

Another issue when diagnosing bipolar disorder in adolescents is the differential diagnosis, distinguishing bipolar disorder from schizophrenia or attention-deficit/hyperactivity disorder (ADHD), conditions that also can present with manic symptoms. "ADHD is much more prevalent in children than bipolar disorder. If you see a child with irritability, it is much more likely to be ADHD." Schizophrenia also poses a diagnostic challenge. "Sometimes, it is only by follow-up of adolescents that makes us confident that the diagnosis is bipolar disorder, compared with schizophrenia."

Adolescents who are accurately diagnosed with bipolar disease will likely require long-term treatment. Dr. Cohen reported his experience with about 60 patients first diagnosed with bipolar disease as adolescents he followed for an average of 8 years. From this group, only five patients did not experience relapses. "When you continue treatment, relapses are fewer and the symptoms remain under better control." But he acknowledged that his experience likely involves a referral bias because his service generally only sees the most severely affected adolescents. He said that he would consider attempting treatment withdrawal from an adolescent patient who has remained mood stabilized on treatment for about 5 years, but he avoids trying treatment withdrawal at times of life with elevated emotional stress, such as when schooling ends or when patients face issues in their sexual relationships.

When bipolar disease is appropriately diagnosed in an adolescent, treatment must be chosen judiciously. Dr. Cohen said he an his associates recently performed a meta-analysis of 41 controlled studies that examined treatment with second-generation antipsychotics in more than 4,000 children and adolescents, including 12 studies that involved youths with bipolar disorder. "Compared with adults, youths were found to be more vulnerable to the adverse effects of second-generation antipsychotics." These adverse effects included somnolence and sedation, weight gain, metabolic changes including prolactin effects, and extrapyramidal motor symptoms. "Tolerability profiles should be considered in making treatment decisions," he said. (see table). Patients who fail to adequately respond to at least two second-generation antipsychotic drugs can be considered candidates for electroconvulsive therapy (ECT).

"In cases of no response to pharmacological treatment, ECT has proven to be safe and effective for both manic and depressive episodes in adolescents with severe illness," Dr. Cohen said. In addition, these patients have generally had favorable reactions to ECT. "Despite negative views about ECT in public opinion, adolescent recipients and their patients share overall positive attitudes toward ECT," he said.

Dr. Cohen said he has received funding from Schering-Plough, Bristol-Myers Squibb. Otsuka, Janssen, Sanofi-Aventis, and Shire.

*9/5/11 -- Dr. Diler's statement and further clarification were added this story.

PARIS – Many psychiatrists have overdiagnosed bipolar disorder in children and adolescents over the past decade, which has led to overly aggressive treatment with second-generation antipsychotic drugs, Dr. David Cohen said at a press briefing at the annual congress of the European College of Neuropsychopharmacology.

This issue might start to resolve with the scheduled publication in 2013 of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), because the current draft establishes a new diagnostic category that Dr. Cohen said is more appropriate for many of these children: temper dysregulation disorder with dysphoria (TDDD).

(c) Mitchel L. Zoler/IMNG

"I’m very pleased that the DSM 5 Working Group intends to improve the way these kids will be characterized by changing the label to TDDD. I think this labeling will help to better characterize this disease and not confuse [these patients] with bipolar disorder," Dr. Cohen said in an interview. Results from follow-up studies suggest that children and adolescents with the spectrum of symptoms included in TDDD, which could also be labeled today as severe mood dysregulation, "may be risk factors for [the diagnosis of] bipolar disorder in adulthood, in perhaps 20% of patients, but many do not develop bipolar disorder," said Dr. Cohen, professor of psychiatry at the University of Paris and head of the department of child and adolescent psychiatry at La Salpêtrière Hospital in Paris.

"I have [results from] long follow-up studies that do not show that manic symptoms in children lead to bipolar disorder" when they become adults. Certain children with symptoms that often characterize bipolar disorder "may be at risk for having bipolar disorder as adults, but not at high rates. Only after a child is 11 or 12 years old and you see these symptoms can you be confident that it is likely bipolar disorder. Adolescence is when" the diagnosis of bipolar can start to be made with any confidence, he said.

"Puberty is a good threshold for talking about bipolar disorder. TDDD is a better diagnosis for pre-pubertal children" because at that stage of life the manic symptoms of bipolar disease, such as irritability, mood change, hyperactivity, and sleep disturbance, can serve as risk markers for the eventual development of bipolar disease, but not at high rates. "Only once a child is at least 11 or 12 years old can you see these symptoms and be confident that it is likely bipolar disease of adolescence or beyond." Adolescence is when the diagnosis of bipolar disease can truly start. A reliable diagnosis of bipolar disorder in a younger child "is really exceptional."

Dr. Cohen’s views are at odds with recent trends in the diagnosis of bipolar disorder among children in the United States. American psychiatrists have, over the past decade, diagnosed bipolar disorder in children as young as age 5 years, resulting in incidence rates that ballooned by as much as four-fold during the 2000s, according to insurance claims data, commented Dr. Rasin Somer Diler, medical director of the Inpatient Child and Adolescent Bipolar Services program at the University of Pittsbugh. Dr. Diler said that in his own program diagnosis rates in younger children have risen by about a third from the late 1990s through the late 2000s, but he added that this was in a referral program that might differ from what has occurred in U.S. community hospitals and office practices.*

This shift in practice has also led to inordinate prescribing of second-generation antipsychotics to children, Dr. Cohen said. "These drugs are only appropriate for bipolar disorder episodes in adolescents."

Psychiatrists "usually use adult criteria to diagnose bipolar disorder" in children and adolescents. "Manic symptoms can be quite frequent in children, but I don’t label them as having bipolar disorder. With manic episodes and bipolar disorder in children you need to see how the symptoms appear over time. You cannot do a proper differential diagnosis in a few days."

Another issue when diagnosing bipolar disorder in adolescents is the differential diagnosis, distinguishing bipolar disorder from schizophrenia or attention-deficit/hyperactivity disorder (ADHD), conditions that also can present with manic symptoms. "ADHD is much more prevalent in children than bipolar disorder. If you see a child with irritability, it is much more likely to be ADHD." Schizophrenia also poses a diagnostic challenge. "Sometimes, it is only by follow-up of adolescents that makes us confident that the diagnosis is bipolar disorder, compared with schizophrenia."

Adolescents who are accurately diagnosed with bipolar disease will likely require long-term treatment. Dr. Cohen reported his experience with about 60 patients first diagnosed with bipolar disease as adolescents he followed for an average of 8 years. From this group, only five patients did not experience relapses. "When you continue treatment, relapses are fewer and the symptoms remain under better control." But he acknowledged that his experience likely involves a referral bias because his service generally only sees the most severely affected adolescents. He said that he would consider attempting treatment withdrawal from an adolescent patient who has remained mood stabilized on treatment for about 5 years, but he avoids trying treatment withdrawal at times of life with elevated emotional stress, such as when schooling ends or when patients face issues in their sexual relationships.

When bipolar disease is appropriately diagnosed in an adolescent, treatment must be chosen judiciously. Dr. Cohen said he an his associates recently performed a meta-analysis of 41 controlled studies that examined treatment with second-generation antipsychotics in more than 4,000 children and adolescents, including 12 studies that involved youths with bipolar disorder. "Compared with adults, youths were found to be more vulnerable to the adverse effects of second-generation antipsychotics." These adverse effects included somnolence and sedation, weight gain, metabolic changes including prolactin effects, and extrapyramidal motor symptoms. "Tolerability profiles should be considered in making treatment decisions," he said. (see table). Patients who fail to adequately respond to at least two second-generation antipsychotic drugs can be considered candidates for electroconvulsive therapy (ECT).

"In cases of no response to pharmacological treatment, ECT has proven to be safe and effective for both manic and depressive episodes in adolescents with severe illness," Dr. Cohen said. In addition, these patients have generally had favorable reactions to ECT. "Despite negative views about ECT in public opinion, adolescent recipients and their patients share overall positive attitudes toward ECT," he said.

Dr. Cohen said he has received funding from Schering-Plough, Bristol-Myers Squibb. Otsuka, Janssen, Sanofi-Aventis, and Shire.

*9/5/11 -- Dr. Diler's statement and further clarification were added this story.

Discuss this article at www.facebook.com/CurrentPsychiatry

Ms. M, age 31, has bipolar I disorder and takes lamotrigine, 200 mg/d, and aripiprazole, 10 mg/d. She was first hospitalized at age 20 for a manic episode and was discharged on lithium, 1,200 mg/d. She was hospitalized again at age 25 for a depressive episode that occurred after she stopped taking lithium because of undesirable side effects. She was switched to lamotrigine, 200 mg/d, which she tolerated well. Aripiprazole, 10 mg/d, was added 1 year later to address emergence of mild mood elevation symptoms.

During a recent follow-up appointment, Ms. M expresses interest in getting pregnant in the next 6 months. Her mood has been stable for 5 years and she asks if she should stop taking her medications in preparation for pregnancy. What would you recommend?

Because the typical age of onset for bipolar disorder (BD) is late adolescence or early adulthood, women are at risk for new onset or recurrence of mood episodes throughout their peak reproductive years. This article updates practitioners on the treatment of BD during pregnancy, including preconception planning and the risks and benefits of medication use during pregnancy. We also cover treatment considerations during the postpartum period, such as prophylaxis of mood episodes and mood stabilizer treatment for women who breast-feed.

Prenatal planning

Ideally, “prenatal planning” should begin long before women with BD prepare to have children. Because one-half of pregnancies in the United States are unplanned¹ and manic episodes may result in impulsivity and increased sexual activity, all women of reproductive age with BD should be counseled about birth control and risks of unplanned pregnancies. Discussions about risks of in utero exposure to psychotropics should occur when medications are first prescribed. Because certain mood stabilizers, (eg, carbamazepine) may decrease efficacy of oral contraceptives by inducing cytochrome P450 (CYP450) enzymes, women taking these medications also should be counseled about additional methods of birth control.²

Oral contraceptives also may affect mood stabilizer levels through similar mechanisms. Because of CYP450 induction, lamotrigine serum levels are lower during the 3 “active” weeks of exposure to exogenous estrogen. During the “pill-free” last week, lamotrigine levels may increase up to 54%.³

Because mood stabilizers such as valproate are associated with teratogenic risks, women with BD should be asked about contraception at every visit.⁴ Valproate also has been associated with an increased risk of menstrual cycle irregularity. Some studies have shown that even before initiating mood stabilizers, women with BD have a higher incidence of menstrual cycle irregularity than women without BD, which suggests the link between polycystic ovarian syndrome (PCOS) and BD may be independent of medications and part of the endophenotype.⁵

The importance of prenatal vitamins should be discussed. The recommended folate dosage for women planning to become pregnant is 0.4 to 1 mg/d and 0.8 to 5 mg/d for women with either a previous pregnancy with neural tube defects or those taking an antiepileptic medication.⁶

Table 1⁷ summarizes recommendations to improve prenatal planning in women with BD. Goals include:

• meeting with the patient at least 3 months before conception to review current menstrual cycle functioning. If your patient exhibits any signs or symptoms of PCOS, consider referral to a gynecologist
• meeting with patient and partner/significant supports to discuss treatment decisions
• optimizing the patient’s mood before conception, preferably for at least 3 to 6 months
• prescribing monotherapy at the lowest therapeutic dose if clinically feasible
• assessing the patient’s personal preferences and beliefs regarding medication use during pregnancy and breast-feeding
• assessing the patient’s capacity to understand the risks and benefits of medication continuation/discontinuation during pregnancy, including risk for relapse, current literature on teratogenicity, perinatal complications, and neurodevelopmental studies. Document that the patient provides informed consent.

Table 1

Pregnancy and BD: Medication management guidelines

CASE CONTINUED: Medication decisions

Ms. M’s first question is, “Should I stop taking my medications?” Ms. M and her psychiatrist review the risks and benefits of medication exposure during pregnancy (Table 2) and decide against discontinuing all medications because of her history of relapse when she stopped lithium. Because Ms. M’s mood has been stable for 5 years, she and her psychiatrist decide to limit her medications to lamotrigine monotherapy at her current dose, and agree to slowly taper aripiprazole. One week later, Ms. M calls and states she has a positive pregnancy test and is wondering if she should stop aripiprazole all at once. Ms. M is advised to continue with the original plan to slowly taper aripiprazole.

Table 2

Potential risks of continuing or discontinuing medications for BD during pregnancy

Medication risks/benefits

Women with BD have a high rate of relapse associated with abrupt discontinuation of pharmacotherapy during pregnancy. As such, patients and their partners and families should be cautioned against rapid discontinuation of medications.⁸ The risk to mother and fetus is particularly high for women with a history of recurrent, severe mood episodes. These patients face not only a high risk of recurrence of mood episodes, but also the inherent danger of impulsivity, poor self-care, and suicidality associated with mania, depression, and mixed states. In these cases, continuing a medication (other than known teratogens such as valproate) that has effectively stabilized mood may be preferred to discontinuation; these decisions are made after careful risk/benefit assessment.

Carefully reviewing the patient’s history is essential to assessing the risks and benefits of tapering medications before pregnancy. Consider the frequency and severity of your patient’s mood episodes, and whether a switch in mood state was rapid or had a prodromal phase. If a patient currently has a stable mood, a history of mild to moderate mood episodes, a history of prodromal symptoms (eg, gradually increasing sleep disturbances and mood deterioration), and no history of rapid switches, gradually discontinuing medications before or during pregnancy may be considered. However, encourage women to enlist their partners and family members to monitor for warning symptoms and advocate for early medication intervention. Because insomnia is a sign of relapse for many patients, educate women and their families about the importance of maintaining a regular sleep/wake cycle and alerting care providers if this cycle changes.

Mood stabilizers with the greatest risk for teratogenicity are valproate, carbamazepine, and lithium.⁹ Valproate is associated with a 6% to 13% risk of congenital malformation, including neural tube defects (1% to 2%) and cardiac or craniofacial defects.³ Risks increase at doses >800 mg/d.¹⁰ Potential perinatal complications associated with valproate include heart rate deceleration, abnormal tone (hypotonia or hypertonia), and growth retardation.¹¹ Neurobehavioral sequelae include lower IQ scores and increased risk of autism.¹²

Carbamazepine is associated with a 2% to 5% risk of congenital malformation, including neural tube defects and cardiac or craniofacial defects.⁴ Perinatal complications associated with carbamazepine include vitamin K deficiency.⁴ The neurobehavioral sequelae of carbamazepine are controversial; most prospective studies do not suggest long-term cognitive deficits.¹³ It is strongly recommended that valproate and carbamazepine be avoided, if possible, in women with BD who plan to become pregnant in the near future.

Prospective studies of lithium have shown a 2.8% rate of congenital malformations, which is much lower than the 11% rate found in retrospective studies.¹⁴ Ebstein’s anomaly—downward displacement of the tricuspid valve—is estimated to occur in .05% to 0.1% of infants exposed to lithium, which is 10 to 20 times the base rate, but a low absolute risk.¹¹

It is recommended women taking lithium during pregnancy complete a fetal high resolution ultrasound and echocardiogram at 16 to 18 weeks.¹¹ Perinatal complications associated with lithium include prematurity, hypotonia, hypothyroidism, hepatic abnormalities, respiratory distress, and nephrogenic diabetes insipidus.¹⁵ When prescribing lithium, divided doses are recommended to maintain a stable serum level. Serum lithium levels should be monitored frequently, and higher doses may be needed because of increased glomerular filtration rate and plasma volume throughout pregnancy.¹⁰ Because of fluid shifts at delivery—including blood loss during delivery and postpartum diuresis and diaphoresis—there is a risk of lithium toxicity at this time. Some researchers have suggested suspending lithium treatment during labor or 24 to 48 hours before planned induction or Caesarean section may lower this risk, with re-administration after delivery when medically stable.¹⁶ Women should be followed closely for signs of lithium toxicity and have lithium levels monitored as clinically indicated.¹⁶ There is insufficient data to support any neurobehavioral sequelae of in utero exposure to lithium; however, there are few long-term follow up studies using standardized measures.¹⁷

Lamotrigine is associated with a 1.9% to 4.6% rate of congenital malformations, including cleft lip/palate (8.9/1,000 vs 0.5 to 1.2/1,000 baseline).⁴ Studies suggest that rates of malformations (cardiac, genitourinary, gastrointestinal, neural tube defect) are dose-dependent: 1.3% at dosages <100 mg/d, 1.9% at 100 to 200 mg/d, and 5.4% at >200 mg/d.¹⁸ Because cleft lip and palate are formed by late second trimester, it is recommended to attempt to keep the lamotrigine dose <200 mg/d during the first and second trimesters. Higher doses of lamotrigine may be needed in the third trimester because of increased renal clearance.¹⁹ There is insufficient data to support any lamotrigine-associated neurobehavioral effects, and unlike studies of valproate, follow-up evaluations of lamotrigine-exposed children have not shown lower IQs.²⁰

Evidence about the reproductive safety of other mood stabilizers used in BD is limited. A recent population-based cohort study did not show increased risk of major malformations in children exposed to topiramate, gabapentin, or oxcarbazepine during the first trimester of pregnancy.²¹ Topiramate often is used in combination with other mood stabilizers for weight control, and studies suggest that polypharmacy with topiramate, especially at higher doses and with valproate, increases the risk of major congenital malformations, especially cleft lip and cleft palate.²² Consequently, topiramate is not recommended for women planning to conceive.

Antipsychotics. Although there is increasing information about outcomes of neonates exposed to atypical antipsychotics during pregnancy, the literature still is limited. The greatest number of studies have evaluated olanzapine, risperidone, and quetiapine and show the rate of congenital malformations is 0.9% to 4.1%, which is consistent with general population rates.^23-26 Perinatal complications associated with these atypical antipsychotics include neonatal extrapyramidal syndrome (EPS), possible neonatal adaptation/withdrawal syndrome, and an increased risk of the infant being either large or small for gestational age. Because atypical antipsychotics may increase the risk of metabolic syndrome, women should be counseled about the possible increased risk for gestational diabetes with these medications. None of these drugs have been associated with neurobehavioral sequelae, but long-term follow-up studies of exposed infants are lacking.

For aripiprazole, asenapine, ziprasidone, iloperidone, and lurasidone there is insufficient data about rate of congenital malformations, obstetric complications, and neurobehavioral sequelae. However, perinatal complications associated with these medications include risk of EPS and withdrawal symptoms.^25,26

CASE CONTINUED: Worsening mood symptoms

During pregnancy, Ms. M’s mood is stable on lamotrigine, 200 mg/d, and she participates in individual interpersonally oriented psychotherapy to address anxieties related to becoming a mother. However, late in her third trimester, Ms. M reports worsening symptoms, including depressed mood, insomnia, fatigue, and poor motivation. She also learns her mother had an episode of postpartum depression. Ms. M and her doctor discuss the risks of postpartum relapse, but she declines additional medication for prophylaxis because she is concerned about its impact on breast-feeding.

Two days after delivery, Ms. M complains of increased insomnia and depressed mood, and her husband reports she is not getting out of bed. She describes thoughts and images of throwing her baby out the window, and feels her thoughts are controlled by something outside of herself. Ms. M suspects her husband is having an affair.

Postpartum risks

All women with BD should be counseled regarding prophylaxis with mood stabilizers during the postpartum period. Women with BD are at high risk of mania and psychosis postpartum, particularly those with a personal or family history of postpartum psychosis. Postpartum psychosis frequently presents with an abrupt onset, shortly after delivery (Table 3). Although it may present with the classic symptoms of mania or psychotic depression, it also may have features of delirium.²⁷

Clinicians should immediately implement treatment with mood stabilizers and antipsychotics to manage acute psychotic symptoms, while also ruling out medical causes or comorbidities. Hospitalization should be considered. Aggressive treatment of insomnia will help stabilize mood. Electroconvulsive therapy can be used in treatment-refractory or urgent cases.¹⁰ Lastly, because approximately 4% of women with postpartum psychosis commit infanticide, all mother/child interactions should be closely supervised.²⁷

In small prospective studies, use of lithium within 48 hours of delivery decreased the risk of relapse of postpartum psychosis within the first 3 months.^28,29 In lower-risk patients who have discontinued pharmacotherapy during pregnancy, restarting medication before or immediately after delivery should be considered. At the same time, it is important to minimize sleep disruption, particularly postpartum. Psychoeducation—ideally begun in the preconception counseling visit—is extremely important for emphasizing the need for postpartum sleep.

Table 3

Consequences of postpartum mood relapse

Breast-feeding concerns

Data on risks of infant exposure to medications through breast milk are largely limited to case reports and case series. All mood-stabilizing medications have been found to pass into breast milk at varying concentrations.²⁸ If a patient chooses to breast-feed, she should inform her pediatrician of this decision, and she and her support system should be educated about signs of neonatal toxicity. Ideally, the psychiatrist should liaise with the patient’s pediatrician, especially when infants are premature, because the child’s liver metabolism may be immature, leading to higher serum drug levels and in some cases drug accumulation. Encourage patients to consider bottle feeding, either their own breast milk, pumped and stored, or formula. This will allow others to assist with feedings and the patient to have more consistent sleep, which could stabilize mood.

Lamotrigine concentrations in breast milk are highly variable.³⁰ Lamotrigine is processed through glucuronidation, a process that is immature in neonates. One study found serum lamotrigine levels in infants were 23% to 33% of maternal serum levels and milk/plasma ratios were highly variable, ranging from 6% to 147%.³⁰ Infants exposed to lamotrigine in breast milk should be monitored for rash and signs of thrombocytosis, and if clinically indicated, lamotrigine levels should be checked.³⁰ Valproate has a low infant serum/maternal serum ratio; there are rare case reports of hepatotoxicity and thrombocytopenia. Although valproate can be reinitiated because of its lower breast milk concentration, it is not a drug of choice in reproductive-age women because of the many issues described above, including risks during pregnancy, PCOS, and effect on oral contraceptives.

Carbamazepine serum levels in breast-feeding infants range from 6% to 65%; hepatic dysfunction, sedation, and poor feeding have been reported in infants in rare instances.³¹

Historically, lithium has been considered incompatible with breast-feeding, but recent reports suggest with careful monitoring it may not be contraindicated. In 10 mother/infant pairs, lithium levels in breast milk and infant serum diminished over time, with no adverse neonatal effects.³² However, if an infant does breast-feed, it may be important to monitor thyroid-stimulating hormone, blood urea nitrogen-to-creatinine ratio, and ECG in both mother and infant, especially if the mother is taking high doses of lithium.

The safety of breast-feeding while treated with atypical antipsychotics is largely unknown. Case reports indicate low transmission of these medications into breast milk.²⁸

CASE CONTINUED

Ms. M is admitted for psychiatric hospitalization because of worsening psychotic symptoms, poor self-care, and persistent thoughts of harming her baby. She agrees to restart aripiprazole, which is titrated to 20 mg/d. Breast-feeding is not pursued. She is discharged in 10 days after she no longer has thoughts of harming her baby, delusions, or psychotic or suicidal ideation. She and her family agree to close supervision by her family and outpatient follow-up.

Related Resources

• The Hospital for Sick Children. Pregnancy and breastfeeding resources. www.motherisk.org/women/pregnancyResources.jsp.
• U.S. National Library of Medicine. TOXNET toxicology data network. http://toxnet.nlm.nih.gov.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Carbamazepine • Equetro, Tegretol
• Gabapentin • Neurontin
• Iloperidone • Fanapt
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Lurasidone • Latuda
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Topiramate • Topamax
• Valproate • Depacon
• Ziprasidone • Geodon

Disclosure

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

Acknowledgement

The authors would like to thank Natasha Barthel, BS, for her assistance with this article.

Discuss this article at www.facebook.com/CurrentPsychiatry

Ms. M, age 31, has bipolar I disorder and takes lamotrigine, 200 mg/d, and aripiprazole, 10 mg/d. She was first hospitalized at age 20 for a manic episode and was discharged on lithium, 1,200 mg/d. She was hospitalized again at age 25 for a depressive episode that occurred after she stopped taking lithium because of undesirable side effects. She was switched to lamotrigine, 200 mg/d, which she tolerated well. Aripiprazole, 10 mg/d, was added 1 year later to address emergence of mild mood elevation symptoms.

During a recent follow-up appointment, Ms. M expresses interest in getting pregnant in the next 6 months. Her mood has been stable for 5 years and she asks if she should stop taking her medications in preparation for pregnancy. What would you recommend?

Because the typical age of onset for bipolar disorder (BD) is late adolescence or early adulthood, women are at risk for new onset or recurrence of mood episodes throughout their peak reproductive years. This article updates practitioners on the treatment of BD during pregnancy, including preconception planning and the risks and benefits of medication use during pregnancy. We also cover treatment considerations during the postpartum period, such as prophylaxis of mood episodes and mood stabilizer treatment for women who breast-feed.

Prenatal planning

Ideally, “prenatal planning” should begin long before women with BD prepare to have children. Because one-half of pregnancies in the United States are unplanned¹ and manic episodes may result in impulsivity and increased sexual activity, all women of reproductive age with BD should be counseled about birth control and risks of unplanned pregnancies. Discussions about risks of in utero exposure to psychotropics should occur when medications are first prescribed. Because certain mood stabilizers, (eg, carbamazepine) may decrease efficacy of oral contraceptives by inducing cytochrome P450 (CYP450) enzymes, women taking these medications also should be counseled about additional methods of birth control.²

Oral contraceptives also may affect mood stabilizer levels through similar mechanisms. Because of CYP450 induction, lamotrigine serum levels are lower during the 3 “active” weeks of exposure to exogenous estrogen. During the “pill-free” last week, lamotrigine levels may increase up to 54%.³

Because mood stabilizers such as valproate are associated with teratogenic risks, women with BD should be asked about contraception at every visit.⁴ Valproate also has been associated with an increased risk of menstrual cycle irregularity. Some studies have shown that even before initiating mood stabilizers, women with BD have a higher incidence of menstrual cycle irregularity than women without BD, which suggests the link between polycystic ovarian syndrome (PCOS) and BD may be independent of medications and part of the endophenotype.⁵

The importance of prenatal vitamins should be discussed. The recommended folate dosage for women planning to become pregnant is 0.4 to 1 mg/d and 0.8 to 5 mg/d for women with either a previous pregnancy with neural tube defects or those taking an antiepileptic medication.⁶

Table 1⁷ summarizes recommendations to improve prenatal planning in women with BD. Goals include:

• meeting with the patient at least 3 months before conception to review current menstrual cycle functioning. If your patient exhibits any signs or symptoms of PCOS, consider referral to a gynecologist
• meeting with patient and partner/significant supports to discuss treatment decisions
• optimizing the patient’s mood before conception, preferably for at least 3 to 6 months
• prescribing monotherapy at the lowest therapeutic dose if clinically feasible
• assessing the patient’s personal preferences and beliefs regarding medication use during pregnancy and breast-feeding
• assessing the patient’s capacity to understand the risks and benefits of medication continuation/discontinuation during pregnancy, including risk for relapse, current literature on teratogenicity, perinatal complications, and neurodevelopmental studies. Document that the patient provides informed consent.

Table 1

Pregnancy and BD: Medication management guidelines

CASE CONTINUED: Medication decisions

Ms. M’s first question is, “Should I stop taking my medications?” Ms. M and her psychiatrist review the risks and benefits of medication exposure during pregnancy (Table 2) and decide against discontinuing all medications because of her history of relapse when she stopped lithium. Because Ms. M’s mood has been stable for 5 years, she and her psychiatrist decide to limit her medications to lamotrigine monotherapy at her current dose, and agree to slowly taper aripiprazole. One week later, Ms. M calls and states she has a positive pregnancy test and is wondering if she should stop aripiprazole all at once. Ms. M is advised to continue with the original plan to slowly taper aripiprazole.

Table 2

Potential risks of continuing or discontinuing medications for BD during pregnancy

Medication risks/benefits

Women with BD have a high rate of relapse associated with abrupt discontinuation of pharmacotherapy during pregnancy. As such, patients and their partners and families should be cautioned against rapid discontinuation of medications.⁸ The risk to mother and fetus is particularly high for women with a history of recurrent, severe mood episodes. These patients face not only a high risk of recurrence of mood episodes, but also the inherent danger of impulsivity, poor self-care, and suicidality associated with mania, depression, and mixed states. In these cases, continuing a medication (other than known teratogens such as valproate) that has effectively stabilized mood may be preferred to discontinuation; these decisions are made after careful risk/benefit assessment.

Carefully reviewing the patient’s history is essential to assessing the risks and benefits of tapering medications before pregnancy. Consider the frequency and severity of your patient’s mood episodes, and whether a switch in mood state was rapid or had a prodromal phase. If a patient currently has a stable mood, a history of mild to moderate mood episodes, a history of prodromal symptoms (eg, gradually increasing sleep disturbances and mood deterioration), and no history of rapid switches, gradually discontinuing medications before or during pregnancy may be considered. However, encourage women to enlist their partners and family members to monitor for warning symptoms and advocate for early medication intervention. Because insomnia is a sign of relapse for many patients, educate women and their families about the importance of maintaining a regular sleep/wake cycle and alerting care providers if this cycle changes.

Mood stabilizers with the greatest risk for teratogenicity are valproate, carbamazepine, and lithium.⁹ Valproate is associated with a 6% to 13% risk of congenital malformation, including neural tube defects (1% to 2%) and cardiac or craniofacial defects.³ Risks increase at doses >800 mg/d.¹⁰ Potential perinatal complications associated with valproate include heart rate deceleration, abnormal tone (hypotonia or hypertonia), and growth retardation.¹¹ Neurobehavioral sequelae include lower IQ scores and increased risk of autism.¹²

Carbamazepine is associated with a 2% to 5% risk of congenital malformation, including neural tube defects and cardiac or craniofacial defects.⁴ Perinatal complications associated with carbamazepine include vitamin K deficiency.⁴ The neurobehavioral sequelae of carbamazepine are controversial; most prospective studies do not suggest long-term cognitive deficits.¹³ It is strongly recommended that valproate and carbamazepine be avoided, if possible, in women with BD who plan to become pregnant in the near future.

Prospective studies of lithium have shown a 2.8% rate of congenital malformations, which is much lower than the 11% rate found in retrospective studies.¹⁴ Ebstein’s anomaly—downward displacement of the tricuspid valve—is estimated to occur in .05% to 0.1% of infants exposed to lithium, which is 10 to 20 times the base rate, but a low absolute risk.¹¹

It is recommended women taking lithium during pregnancy complete a fetal high resolution ultrasound and echocardiogram at 16 to 18 weeks.¹¹ Perinatal complications associated with lithium include prematurity, hypotonia, hypothyroidism, hepatic abnormalities, respiratory distress, and nephrogenic diabetes insipidus.¹⁵ When prescribing lithium, divided doses are recommended to maintain a stable serum level. Serum lithium levels should be monitored frequently, and higher doses may be needed because of increased glomerular filtration rate and plasma volume throughout pregnancy.¹⁰ Because of fluid shifts at delivery—including blood loss during delivery and postpartum diuresis and diaphoresis—there is a risk of lithium toxicity at this time. Some researchers have suggested suspending lithium treatment during labor or 24 to 48 hours before planned induction or Caesarean section may lower this risk, with re-administration after delivery when medically stable.¹⁶ Women should be followed closely for signs of lithium toxicity and have lithium levels monitored as clinically indicated.¹⁶ There is insufficient data to support any neurobehavioral sequelae of in utero exposure to lithium; however, there are few long-term follow up studies using standardized measures.¹⁷

Lamotrigine is associated with a 1.9% to 4.6% rate of congenital malformations, including cleft lip/palate (8.9/1,000 vs 0.5 to 1.2/1,000 baseline).⁴ Studies suggest that rates of malformations (cardiac, genitourinary, gastrointestinal, neural tube defect) are dose-dependent: 1.3% at dosages <100 mg/d, 1.9% at 100 to 200 mg/d, and 5.4% at >200 mg/d.¹⁸ Because cleft lip and palate are formed by late second trimester, it is recommended to attempt to keep the lamotrigine dose <200 mg/d during the first and second trimesters. Higher doses of lamotrigine may be needed in the third trimester because of increased renal clearance.¹⁹ There is insufficient data to support any lamotrigine-associated neurobehavioral effects, and unlike studies of valproate, follow-up evaluations of lamotrigine-exposed children have not shown lower IQs.²⁰

Evidence about the reproductive safety of other mood stabilizers used in BD is limited. A recent population-based cohort study did not show increased risk of major malformations in children exposed to topiramate, gabapentin, or oxcarbazepine during the first trimester of pregnancy.²¹ Topiramate often is used in combination with other mood stabilizers for weight control, and studies suggest that polypharmacy with topiramate, especially at higher doses and with valproate, increases the risk of major congenital malformations, especially cleft lip and cleft palate.²² Consequently, topiramate is not recommended for women planning to conceive.

Antipsychotics. Although there is increasing information about outcomes of neonates exposed to atypical antipsychotics during pregnancy, the literature still is limited. The greatest number of studies have evaluated olanzapine, risperidone, and quetiapine and show the rate of congenital malformations is 0.9% to 4.1%, which is consistent with general population rates.^23-26 Perinatal complications associated with these atypical antipsychotics include neonatal extrapyramidal syndrome (EPS), possible neonatal adaptation/withdrawal syndrome, and an increased risk of the infant being either large or small for gestational age. Because atypical antipsychotics may increase the risk of metabolic syndrome, women should be counseled about the possible increased risk for gestational diabetes with these medications. None of these drugs have been associated with neurobehavioral sequelae, but long-term follow-up studies of exposed infants are lacking.

For aripiprazole, asenapine, ziprasidone, iloperidone, and lurasidone there is insufficient data about rate of congenital malformations, obstetric complications, and neurobehavioral sequelae. However, perinatal complications associated with these medications include risk of EPS and withdrawal symptoms.^25,26

CASE CONTINUED: Worsening mood symptoms

During pregnancy, Ms. M’s mood is stable on lamotrigine, 200 mg/d, and she participates in individual interpersonally oriented psychotherapy to address anxieties related to becoming a mother. However, late in her third trimester, Ms. M reports worsening symptoms, including depressed mood, insomnia, fatigue, and poor motivation. She also learns her mother had an episode of postpartum depression. Ms. M and her doctor discuss the risks of postpartum relapse, but she declines additional medication for prophylaxis because she is concerned about its impact on breast-feeding.

Two days after delivery, Ms. M complains of increased insomnia and depressed mood, and her husband reports she is not getting out of bed. She describes thoughts and images of throwing her baby out the window, and feels her thoughts are controlled by something outside of herself. Ms. M suspects her husband is having an affair.

Postpartum risks

All women with BD should be counseled regarding prophylaxis with mood stabilizers during the postpartum period. Women with BD are at high risk of mania and psychosis postpartum, particularly those with a personal or family history of postpartum psychosis. Postpartum psychosis frequently presents with an abrupt onset, shortly after delivery (Table 3). Although it may present with the classic symptoms of mania or psychotic depression, it also may have features of delirium.²⁷

Clinicians should immediately implement treatment with mood stabilizers and antipsychotics to manage acute psychotic symptoms, while also ruling out medical causes or comorbidities. Hospitalization should be considered. Aggressive treatment of insomnia will help stabilize mood. Electroconvulsive therapy can be used in treatment-refractory or urgent cases.¹⁰ Lastly, because approximately 4% of women with postpartum psychosis commit infanticide, all mother/child interactions should be closely supervised.²⁷

In small prospective studies, use of lithium within 48 hours of delivery decreased the risk of relapse of postpartum psychosis within the first 3 months.^28,29 In lower-risk patients who have discontinued pharmacotherapy during pregnancy, restarting medication before or immediately after delivery should be considered. At the same time, it is important to minimize sleep disruption, particularly postpartum. Psychoeducation—ideally begun in the preconception counseling visit—is extremely important for emphasizing the need for postpartum sleep.

Table 3

Consequences of postpartum mood relapse

Breast-feeding concerns

Data on risks of infant exposure to medications through breast milk are largely limited to case reports and case series. All mood-stabilizing medications have been found to pass into breast milk at varying concentrations.²⁸ If a patient chooses to breast-feed, she should inform her pediatrician of this decision, and she and her support system should be educated about signs of neonatal toxicity. Ideally, the psychiatrist should liaise with the patient’s pediatrician, especially when infants are premature, because the child’s liver metabolism may be immature, leading to higher serum drug levels and in some cases drug accumulation. Encourage patients to consider bottle feeding, either their own breast milk, pumped and stored, or formula. This will allow others to assist with feedings and the patient to have more consistent sleep, which could stabilize mood.

Lamotrigine concentrations in breast milk are highly variable.³⁰ Lamotrigine is processed through glucuronidation, a process that is immature in neonates. One study found serum lamotrigine levels in infants were 23% to 33% of maternal serum levels and milk/plasma ratios were highly variable, ranging from 6% to 147%.³⁰ Infants exposed to lamotrigine in breast milk should be monitored for rash and signs of thrombocytosis, and if clinically indicated, lamotrigine levels should be checked.³⁰ Valproate has a low infant serum/maternal serum ratio; there are rare case reports of hepatotoxicity and thrombocytopenia. Although valproate can be reinitiated because of its lower breast milk concentration, it is not a drug of choice in reproductive-age women because of the many issues described above, including risks during pregnancy, PCOS, and effect on oral contraceptives.

Carbamazepine serum levels in breast-feeding infants range from 6% to 65%; hepatic dysfunction, sedation, and poor feeding have been reported in infants in rare instances.³¹

Historically, lithium has been considered incompatible with breast-feeding, but recent reports suggest with careful monitoring it may not be contraindicated. In 10 mother/infant pairs, lithium levels in breast milk and infant serum diminished over time, with no adverse neonatal effects.³² However, if an infant does breast-feed, it may be important to monitor thyroid-stimulating hormone, blood urea nitrogen-to-creatinine ratio, and ECG in both mother and infant, especially if the mother is taking high doses of lithium.

The safety of breast-feeding while treated with atypical antipsychotics is largely unknown. Case reports indicate low transmission of these medications into breast milk.²⁸

CASE CONTINUED

Ms. M is admitted for psychiatric hospitalization because of worsening psychotic symptoms, poor self-care, and persistent thoughts of harming her baby. She agrees to restart aripiprazole, which is titrated to 20 mg/d. Breast-feeding is not pursued. She is discharged in 10 days after she no longer has thoughts of harming her baby, delusions, or psychotic or suicidal ideation. She and her family agree to close supervision by her family and outpatient follow-up.

Related Resources

• The Hospital for Sick Children. Pregnancy and breastfeeding resources. www.motherisk.org/women/pregnancyResources.jsp.
• U.S. National Library of Medicine. TOXNET toxicology data network. http://toxnet.nlm.nih.gov.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Carbamazepine • Equetro, Tegretol
• Gabapentin • Neurontin
• Iloperidone • Fanapt
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Lurasidone • Latuda
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Topiramate • Topamax
• Valproate • Depacon
• Ziprasidone • Geodon

Disclosure

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

Acknowledgement

The authors would like to thank Natasha Barthel, BS, for her assistance with this article.

Discuss this article at www.facebook.com/CurrentPsychiatry

Ms. M, age 31, has bipolar I disorder and takes lamotrigine, 200 mg/d, and aripiprazole, 10 mg/d. She was first hospitalized at age 20 for a manic episode and was discharged on lithium, 1,200 mg/d. She was hospitalized again at age 25 for a depressive episode that occurred after she stopped taking lithium because of undesirable side effects. She was switched to lamotrigine, 200 mg/d, which she tolerated well. Aripiprazole, 10 mg/d, was added 1 year later to address emergence of mild mood elevation symptoms.

During a recent follow-up appointment, Ms. M expresses interest in getting pregnant in the next 6 months. Her mood has been stable for 5 years and she asks if she should stop taking her medications in preparation for pregnancy. What would you recommend?

Because the typical age of onset for bipolar disorder (BD) is late adolescence or early adulthood, women are at risk for new onset or recurrence of mood episodes throughout their peak reproductive years. This article updates practitioners on the treatment of BD during pregnancy, including preconception planning and the risks and benefits of medication use during pregnancy. We also cover treatment considerations during the postpartum period, such as prophylaxis of mood episodes and mood stabilizer treatment for women who breast-feed.

Prenatal planning

Ideally, “prenatal planning” should begin long before women with BD prepare to have children. Because one-half of pregnancies in the United States are unplanned¹ and manic episodes may result in impulsivity and increased sexual activity, all women of reproductive age with BD should be counseled about birth control and risks of unplanned pregnancies. Discussions about risks of in utero exposure to psychotropics should occur when medications are first prescribed. Because certain mood stabilizers, (eg, carbamazepine) may decrease efficacy of oral contraceptives by inducing cytochrome P450 (CYP450) enzymes, women taking these medications also should be counseled about additional methods of birth control.²

Oral contraceptives also may affect mood stabilizer levels through similar mechanisms. Because of CYP450 induction, lamotrigine serum levels are lower during the 3 “active” weeks of exposure to exogenous estrogen. During the “pill-free” last week, lamotrigine levels may increase up to 54%.³

Because mood stabilizers such as valproate are associated with teratogenic risks, women with BD should be asked about contraception at every visit.⁴ Valproate also has been associated with an increased risk of menstrual cycle irregularity. Some studies have shown that even before initiating mood stabilizers, women with BD have a higher incidence of menstrual cycle irregularity than women without BD, which suggests the link between polycystic ovarian syndrome (PCOS) and BD may be independent of medications and part of the endophenotype.⁵

The importance of prenatal vitamins should be discussed. The recommended folate dosage for women planning to become pregnant is 0.4 to 1 mg/d and 0.8 to 5 mg/d for women with either a previous pregnancy with neural tube defects or those taking an antiepileptic medication.⁶

Table 1⁷ summarizes recommendations to improve prenatal planning in women with BD. Goals include:

• meeting with the patient at least 3 months before conception to review current menstrual cycle functioning. If your patient exhibits any signs or symptoms of PCOS, consider referral to a gynecologist
• meeting with patient and partner/significant supports to discuss treatment decisions
• optimizing the patient’s mood before conception, preferably for at least 3 to 6 months
• prescribing monotherapy at the lowest therapeutic dose if clinically feasible
• assessing the patient’s personal preferences and beliefs regarding medication use during pregnancy and breast-feeding
• assessing the patient’s capacity to understand the risks and benefits of medication continuation/discontinuation during pregnancy, including risk for relapse, current literature on teratogenicity, perinatal complications, and neurodevelopmental studies. Document that the patient provides informed consent.

Table 1

Pregnancy and BD: Medication management guidelines

CASE CONTINUED: Medication decisions

Ms. M’s first question is, “Should I stop taking my medications?” Ms. M and her psychiatrist review the risks and benefits of medication exposure during pregnancy (Table 2) and decide against discontinuing all medications because of her history of relapse when she stopped lithium. Because Ms. M’s mood has been stable for 5 years, she and her psychiatrist decide to limit her medications to lamotrigine monotherapy at her current dose, and agree to slowly taper aripiprazole. One week later, Ms. M calls and states she has a positive pregnancy test and is wondering if she should stop aripiprazole all at once. Ms. M is advised to continue with the original plan to slowly taper aripiprazole.

Table 2

Potential risks of continuing or discontinuing medications for BD during pregnancy

Medication risks/benefits

Women with BD have a high rate of relapse associated with abrupt discontinuation of pharmacotherapy during pregnancy. As such, patients and their partners and families should be cautioned against rapid discontinuation of medications.⁸ The risk to mother and fetus is particularly high for women with a history of recurrent, severe mood episodes. These patients face not only a high risk of recurrence of mood episodes, but also the inherent danger of impulsivity, poor self-care, and suicidality associated with mania, depression, and mixed states. In these cases, continuing a medication (other than known teratogens such as valproate) that has effectively stabilized mood may be preferred to discontinuation; these decisions are made after careful risk/benefit assessment.

Carefully reviewing the patient’s history is essential to assessing the risks and benefits of tapering medications before pregnancy. Consider the frequency and severity of your patient’s mood episodes, and whether a switch in mood state was rapid or had a prodromal phase. If a patient currently has a stable mood, a history of mild to moderate mood episodes, a history of prodromal symptoms (eg, gradually increasing sleep disturbances and mood deterioration), and no history of rapid switches, gradually discontinuing medications before or during pregnancy may be considered. However, encourage women to enlist their partners and family members to monitor for warning symptoms and advocate for early medication intervention. Because insomnia is a sign of relapse for many patients, educate women and their families about the importance of maintaining a regular sleep/wake cycle and alerting care providers if this cycle changes.

Mood stabilizers with the greatest risk for teratogenicity are valproate, carbamazepine, and lithium.⁹ Valproate is associated with a 6% to 13% risk of congenital malformation, including neural tube defects (1% to 2%) and cardiac or craniofacial defects.³ Risks increase at doses >800 mg/d.¹⁰ Potential perinatal complications associated with valproate include heart rate deceleration, abnormal tone (hypotonia or hypertonia), and growth retardation.¹¹ Neurobehavioral sequelae include lower IQ scores and increased risk of autism.¹²

Carbamazepine is associated with a 2% to 5% risk of congenital malformation, including neural tube defects and cardiac or craniofacial defects.⁴ Perinatal complications associated with carbamazepine include vitamin K deficiency.⁴ The neurobehavioral sequelae of carbamazepine are controversial; most prospective studies do not suggest long-term cognitive deficits.¹³ It is strongly recommended that valproate and carbamazepine be avoided, if possible, in women with BD who plan to become pregnant in the near future.

Prospective studies of lithium have shown a 2.8% rate of congenital malformations, which is much lower than the 11% rate found in retrospective studies.¹⁴ Ebstein’s anomaly—downward displacement of the tricuspid valve—is estimated to occur in .05% to 0.1% of infants exposed to lithium, which is 10 to 20 times the base rate, but a low absolute risk.¹¹

It is recommended women taking lithium during pregnancy complete a fetal high resolution ultrasound and echocardiogram at 16 to 18 weeks.¹¹ Perinatal complications associated with lithium include prematurity, hypotonia, hypothyroidism, hepatic abnormalities, respiratory distress, and nephrogenic diabetes insipidus.¹⁵ When prescribing lithium, divided doses are recommended to maintain a stable serum level. Serum lithium levels should be monitored frequently, and higher doses may be needed because of increased glomerular filtration rate and plasma volume throughout pregnancy.¹⁰ Because of fluid shifts at delivery—including blood loss during delivery and postpartum diuresis and diaphoresis—there is a risk of lithium toxicity at this time. Some researchers have suggested suspending lithium treatment during labor or 24 to 48 hours before planned induction or Caesarean section may lower this risk, with re-administration after delivery when medically stable.¹⁶ Women should be followed closely for signs of lithium toxicity and have lithium levels monitored as clinically indicated.¹⁶ There is insufficient data to support any neurobehavioral sequelae of in utero exposure to lithium; however, there are few long-term follow up studies using standardized measures.¹⁷

Lamotrigine is associated with a 1.9% to 4.6% rate of congenital malformations, including cleft lip/palate (8.9/1,000 vs 0.5 to 1.2/1,000 baseline).⁴ Studies suggest that rates of malformations (cardiac, genitourinary, gastrointestinal, neural tube defect) are dose-dependent: 1.3% at dosages <100 mg/d, 1.9% at 100 to 200 mg/d, and 5.4% at >200 mg/d.¹⁸ Because cleft lip and palate are formed by late second trimester, it is recommended to attempt to keep the lamotrigine dose <200 mg/d during the first and second trimesters. Higher doses of lamotrigine may be needed in the third trimester because of increased renal clearance.¹⁹ There is insufficient data to support any lamotrigine-associated neurobehavioral effects, and unlike studies of valproate, follow-up evaluations of lamotrigine-exposed children have not shown lower IQs.²⁰

Evidence about the reproductive safety of other mood stabilizers used in BD is limited. A recent population-based cohort study did not show increased risk of major malformations in children exposed to topiramate, gabapentin, or oxcarbazepine during the first trimester of pregnancy.²¹ Topiramate often is used in combination with other mood stabilizers for weight control, and studies suggest that polypharmacy with topiramate, especially at higher doses and with valproate, increases the risk of major congenital malformations, especially cleft lip and cleft palate.²² Consequently, topiramate is not recommended for women planning to conceive.

Antipsychotics. Although there is increasing information about outcomes of neonates exposed to atypical antipsychotics during pregnancy, the literature still is limited. The greatest number of studies have evaluated olanzapine, risperidone, and quetiapine and show the rate of congenital malformations is 0.9% to 4.1%, which is consistent with general population rates.^23-26 Perinatal complications associated with these atypical antipsychotics include neonatal extrapyramidal syndrome (EPS), possible neonatal adaptation/withdrawal syndrome, and an increased risk of the infant being either large or small for gestational age. Because atypical antipsychotics may increase the risk of metabolic syndrome, women should be counseled about the possible increased risk for gestational diabetes with these medications. None of these drugs have been associated with neurobehavioral sequelae, but long-term follow-up studies of exposed infants are lacking.

For aripiprazole, asenapine, ziprasidone, iloperidone, and lurasidone there is insufficient data about rate of congenital malformations, obstetric complications, and neurobehavioral sequelae. However, perinatal complications associated with these medications include risk of EPS and withdrawal symptoms.^25,26

CASE CONTINUED: Worsening mood symptoms

During pregnancy, Ms. M’s mood is stable on lamotrigine, 200 mg/d, and she participates in individual interpersonally oriented psychotherapy to address anxieties related to becoming a mother. However, late in her third trimester, Ms. M reports worsening symptoms, including depressed mood, insomnia, fatigue, and poor motivation. She also learns her mother had an episode of postpartum depression. Ms. M and her doctor discuss the risks of postpartum relapse, but she declines additional medication for prophylaxis because she is concerned about its impact on breast-feeding.

Two days after delivery, Ms. M complains of increased insomnia and depressed mood, and her husband reports she is not getting out of bed. She describes thoughts and images of throwing her baby out the window, and feels her thoughts are controlled by something outside of herself. Ms. M suspects her husband is having an affair.

Postpartum risks

All women with BD should be counseled regarding prophylaxis with mood stabilizers during the postpartum period. Women with BD are at high risk of mania and psychosis postpartum, particularly those with a personal or family history of postpartum psychosis. Postpartum psychosis frequently presents with an abrupt onset, shortly after delivery (Table 3). Although it may present with the classic symptoms of mania or psychotic depression, it also may have features of delirium.²⁷

Clinicians should immediately implement treatment with mood stabilizers and antipsychotics to manage acute psychotic symptoms, while also ruling out medical causes or comorbidities. Hospitalization should be considered. Aggressive treatment of insomnia will help stabilize mood. Electroconvulsive therapy can be used in treatment-refractory or urgent cases.¹⁰ Lastly, because approximately 4% of women with postpartum psychosis commit infanticide, all mother/child interactions should be closely supervised.²⁷

In small prospective studies, use of lithium within 48 hours of delivery decreased the risk of relapse of postpartum psychosis within the first 3 months.^28,29 In lower-risk patients who have discontinued pharmacotherapy during pregnancy, restarting medication before or immediately after delivery should be considered. At the same time, it is important to minimize sleep disruption, particularly postpartum. Psychoeducation—ideally begun in the preconception counseling visit—is extremely important for emphasizing the need for postpartum sleep.

Table 3

Consequences of postpartum mood relapse

Breast-feeding concerns

Data on risks of infant exposure to medications through breast milk are largely limited to case reports and case series. All mood-stabilizing medications have been found to pass into breast milk at varying concentrations.²⁸ If a patient chooses to breast-feed, she should inform her pediatrician of this decision, and she and her support system should be educated about signs of neonatal toxicity. Ideally, the psychiatrist should liaise with the patient’s pediatrician, especially when infants are premature, because the child’s liver metabolism may be immature, leading to higher serum drug levels and in some cases drug accumulation. Encourage patients to consider bottle feeding, either their own breast milk, pumped and stored, or formula. This will allow others to assist with feedings and the patient to have more consistent sleep, which could stabilize mood.

Lamotrigine concentrations in breast milk are highly variable.³⁰ Lamotrigine is processed through glucuronidation, a process that is immature in neonates. One study found serum lamotrigine levels in infants were 23% to 33% of maternal serum levels and milk/plasma ratios were highly variable, ranging from 6% to 147%.³⁰ Infants exposed to lamotrigine in breast milk should be monitored for rash and signs of thrombocytosis, and if clinically indicated, lamotrigine levels should be checked.³⁰ Valproate has a low infant serum/maternal serum ratio; there are rare case reports of hepatotoxicity and thrombocytopenia. Although valproate can be reinitiated because of its lower breast milk concentration, it is not a drug of choice in reproductive-age women because of the many issues described above, including risks during pregnancy, PCOS, and effect on oral contraceptives.

Carbamazepine serum levels in breast-feeding infants range from 6% to 65%; hepatic dysfunction, sedation, and poor feeding have been reported in infants in rare instances.³¹

Historically, lithium has been considered incompatible with breast-feeding, but recent reports suggest with careful monitoring it may not be contraindicated. In 10 mother/infant pairs, lithium levels in breast milk and infant serum diminished over time, with no adverse neonatal effects.³² However, if an infant does breast-feed, it may be important to monitor thyroid-stimulating hormone, blood urea nitrogen-to-creatinine ratio, and ECG in both mother and infant, especially if the mother is taking high doses of lithium.

The safety of breast-feeding while treated with atypical antipsychotics is largely unknown. Case reports indicate low transmission of these medications into breast milk.²⁸

CASE CONTINUED

Ms. M is admitted for psychiatric hospitalization because of worsening psychotic symptoms, poor self-care, and persistent thoughts of harming her baby. She agrees to restart aripiprazole, which is titrated to 20 mg/d. Breast-feeding is not pursued. She is discharged in 10 days after she no longer has thoughts of harming her baby, delusions, or psychotic or suicidal ideation. She and her family agree to close supervision by her family and outpatient follow-up.

Related Resources

• The Hospital for Sick Children. Pregnancy and breastfeeding resources. www.motherisk.org/women/pregnancyResources.jsp.
• U.S. National Library of Medicine. TOXNET toxicology data network. http://toxnet.nlm.nih.gov.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Carbamazepine • Equetro, Tegretol
• Gabapentin • Neurontin
• Iloperidone • Fanapt
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Lurasidone • Latuda
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Topiramate • Topamax
• Valproate • Depacon
• Ziprasidone • Geodon

Disclosure

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

Acknowledgement

The authors would like to thank Natasha Barthel, BS, for her assistance with this article.