A 61-year-old man presents for evaluation of new-onset cognitive impairment, which has developed over the past 6 to 8 months. He has bipolar disorder, for which he has been taking lithium carbonate (Eskalith) for the past 15 years. This therapy kept his mood stable until a relapse of depression and mania 1 year ago required hospitalization and an increase in the lithium dose, which was then lowered somewhat after he improved (see below). His cognitive symptoms appeared gradually within 2 months after his release from the hospital.

He now has difficulty concentrating, a tendency to substitute words incorrectly during conversation, and difficulty recalling names and “retrieving memories.” He also reports a worsening tremor in his dominant hand that compromises his ability to eat with a spoon or a fork. He complains of increasing daytime somnolence, which began when his lithium dose was increased and improved when the dose was decreased.

The patient is a mathematician and recently finished revising the curriculum for an undergraduate course in advanced mathematics that he teaches. He does not smoke cigarettes, and he drinks alcohol only socially. He has no other medical conditions and no known cardiovascular risk factors.

Current and recent medications

• Lithium carbonate 600 mg twice daily (before his hospitalization he had been taking 600 mg twice daily; this was increased to 1,500 mg/day during the hospitalization and then decreased to the current dose as maintenance therapy)
• Divalproex (Depakote) 250 mg every night
• Gabapentin (Neurontin) 400 mg every night (the dosages of divalproex and gabapentin have remained unchanged since before his hospitalization)
• A multivitamin daily
• Naproxen (Naprosyn, Aleve) 250 mg up to two times a week for arthritic knee pain
• Aripiprazole (Abilify). This antipsychotic drug was recently discontinued because of parkinsonian symptoms, which then gradually improved.
• Memantine (Namenda), which is indicated for the treatment of moderate to severe Alzheimer disease. The patient reports that he stopped taking it after 3 weeks because he did not perceive it to be helping.

THE INITIAL EVALUATION

Physical examination

Temperature 98.3°F (36.8°C), pulse 60 beats per minute, respirations 16 per minute, blood pressure 126/64 mm Hg sitting and 118/71 mm Hg standing.

The patient is well groomed, alert, and cooperative. His head, eyes, ears, nose, and throat are normal. His teeth are in good condition. His skin is normal. We note no thyromegaly, carotid bruits, or palpable lymphadenopathy. His lungs are clear to auscultation. Results of cardiac, abdominal, and musculoskeletal examinations are all normal.

His deep tendon reflexes, sensory and motor testing, and gait are normal. The cerebellar examination is normal, aside from a mild tremor in his right hand when it is outstretched, with no resting tremor or cogwheel rigidity.

On the Mini-Mental State Examination (MMSE) he scores a perfect 30/30 (normal 24–30). He can draw a clock normally. His score on the short-form Geriatric Depression Scale is 4/15 (a score of 6 or higher indicates depression).

Laboratory tests

• Serum lithium level 0.8 mmol/L (therapeutic range 0.5–1.5 mmol/L) (his previous values are not available)
• Thyroid-stimulating hormone level 1.61 μU/mL (normal 0.40–5.50)
• Complete blood cell count and comprehensive metabolic panel values are within normal limits.

Magnetic resonance imaging

Noncontrast magnetic resonance imaging of the head reveals two nonspecific punctate foci of high signal intensity on T2-weighted images in the left frontal white matter, but the results are otherwise normal.

DIFFERENTIAL DIAGNOSIS

1. On the basis of this information, which is the most likely cause of this patient’s cogitive impairment?

• Dementia with Lewy bodies
• Early-onset Alzheimer disease
• Stroke with vascular cognitive impairment
• Lithium neurotoxicity

Lithium neurotoxicity is the most likely cause of this patient’s symptoms, given the temporal relationship between the adjusting of his lithium dose and the onset of his symptoms. Lithium therapy causes subtle cognitive deficits. Its dosing in older patients requires careful monitoring because of age-related alterations in its pharmacology and its various drug interactions; both mechanisms played a role in precipitating lithium toxicity in this patient.

Although his lithium levels are in the broadly accepted therapeutic range, there is much debate about the best maintenance level for patients with bipolar disorder. A level in the range of 1 to 1.2 mmol/L may be best in acute mania, while a lower level of around 0.8 mmol/L is preferred in the depressive phase. Once the patient’s mood has stabilized, the best maintenance level may be in the range of 0.2 to 0.6 mmol/L.

Dementia with Lewy bodies, although suggested by the patient’s cognitive impairment, history of parkinsonian symptoms, and somnolence, is an unlikely cause because his motor symptoms resolved after the aripiprazole was discontinued, his somnolence improved after the dose of lithium was reduced, and his alertness did not fluctuate thereafter as would be expected in dementia with Lewy bodies.

Alzheimer disease usually manifests as gradually progressive cognitive deficits involving memory impairment with one or more of the following: aphasia, apraxia, agnosia, and disturbance in executive functioning. In contrast, this patient’s memory loss was fairly abrupt and not slowly progressive.

Stroke is also unlikely, as he has no history of stroke or focal neurologic deficits. Although a magnetic resonance scan of the brain showed some evidence of small-vessel ischemic changes, it showed no cortical infarcts.

MECHANISMS OF LITHIUM NEUROTOXICITY

2. What are the possible mechanisms of lithium neurotoxicity in this patient?

• The increased dose of lithium
• The interaction of nonsteroidal anti-inflammatory drugs (NSAIDs) and lithium
• The interaction of the other psychotropic medications with lithium
• All of the above
• None of the above

All of the above could be contributing.

Although lithium is thought to cause side effects in as many as 60% of patients of any age who take it, the rate of serious adverse effects is reportedly higher in older patients than in younger patients.¹

That said, cognitive deficits are common in bipolar disorder irrespective of lithium use.

COGNITIVE IMPAIRMENT IN BIPOLAR DISORDER

3. If cognitive impairment in bipolar disorder is common, when does it occur?

• Only in the remission phase
• Only in the manic phase
• Only in the depression phase
• In all phases of the disease

Cognitive impairment occurs in all phases of bipolar disorder. Neuropsychological testing of bipolar patients in remission uncovers subtle, persistent cognitive impairment in executive function and in visuospatial memory without mood symptoms.^3–5 Impaired executive functioning, predominantly frontal lobe dysfunction, interferes with one’s ability to initiate, plan, perform, and successfully complete a task and challenges one’s ability to function effectively in society and to comply with medical advice and instructions on taking medications.

RECOMMENDATIONS

4. What should we recommend to this patient?

• Decrease the current dose of lithium
• Stop all medications
• Undergo detailed neuropsychological testing
• Follow up with a psychiatrist, if needed

The patient’s lithium level was within the therapeutic range and his bipolar symptoms were well controlled. In older patients, however, the optimal serum level of lithium is often unclear, making it advisable to reduce the dose when an adverse effect is suspected.

His other medications should be reviewed. Gabapentin is not indicated for use as a mood stabilizer, and his divalproex dose (250 mg) is well below the usual therapeutic dose of 1,000 to 2,000 mg/day.⁶ The gabapentin could be discontinued, and the divalproex could be increased to a therapeutic dose.

NSAIDs can increase serum lithium levels, diminish renal lithium clearance, and possibly induce lithium toxicity, but the effect varies considerably among drugs and individuals.⁷ We would advise this patient to stop taking naproxen and switch to acetaminophen (Tylenol) for his arthritis pain, and we would inform him of the risk of lithium toxicity with continuous use of NSAIDs.

We would also recommend additional neuropsychological testing. The patient noticed subtle difficulties in his cognitive abilities that were not apparent on the MMSE. While the MMSE is an acceptable cognitive test, it is often not sensitive enough to detect milder forms of cognitive impairment, especially in well-educated patients at the usual cut-point of 24. A comprehensive neuropsychological examination is a more sensitive measure of cognition, involving the detailed testing of various cognitive domains. It can reveal a pattern of cognitive impairment that helps to differentiate between normal and mood disorders and also can detect subtle executive dysfunction.

However, detailed neuropsychological testing is time-consuming and may not be obtained rapidly enough to help in making clinical decisions quickly. In this patient’s case, immediate collaboration and follow-up with the patient’s psychiatrist would be the most expeditious way to reassess the patient’s medication regimen.

FOLLOW-UP COURSE

We informed the patient’s psychiatrist that we thought the patient had increased sensitivity to lithium (even at “therapeutic” levels), possibly related to a drug-drug interaction.

His dose of lithium was kept at 600 mg twice daily, as the lithium toxicity was most likely due to a drug-drug interaction.

We discontinued his memantine, since he did not have Alzheimer disease and since he wasn’t taking it anyway. He continued taking gabapentin and divalproex at the same doses, and he stopped taking naproxyn and substituted acetaminophen for his arthritis pain. We advised him about about health maintenance, including proper nutrition, mineral and vitamin supplements, and exercise.

The patient underwent neuropsychological testing to better characterize his cognitive impairment. The findings did not suggest dementia, but were consistent with minor cognitive deficits caused by lithium.

When seen at a follow-up visit 6 weeks later the patient was free of symptoms except for the tremor in his dominant hand. His mood was stable and his cognition was better. No further changes were required in his psychotropic drug regimen.

TAKE-HOME POINTS

When a bipolar patient develops acute changes in cognition, we should suspect adverse effects of lithium as the cause, because of its narrow therapeutic window and interactions with other prescribed drugs. The case presented here reminds us to consider adverse drug effects any time an older patient develops acute changes in cognition. One should also consider the potential for a drug-drug interaction when reviewing the patient’s medication list and be especially vigilant in monitoring patients taking lithium, since its safety and effectiveness are affected by aging and by the co-administration of drugs that influence its clearance.

Despite these caveats, lithium remains an effective treatment in elderly patients, provided we are aware of the risks and benefits of its use.

A 61-year-old man presents for evaluation of new-onset cognitive impairment, which has developed over the past 6 to 8 months. He has bipolar disorder, for which he has been taking lithium carbonate (Eskalith) for the past 15 years. This therapy kept his mood stable until a relapse of depression and mania 1 year ago required hospitalization and an increase in the lithium dose, which was then lowered somewhat after he improved (see below). His cognitive symptoms appeared gradually within 2 months after his release from the hospital.

He now has difficulty concentrating, a tendency to substitute words incorrectly during conversation, and difficulty recalling names and “retrieving memories.” He also reports a worsening tremor in his dominant hand that compromises his ability to eat with a spoon or a fork. He complains of increasing daytime somnolence, which began when his lithium dose was increased and improved when the dose was decreased.

The patient is a mathematician and recently finished revising the curriculum for an undergraduate course in advanced mathematics that he teaches. He does not smoke cigarettes, and he drinks alcohol only socially. He has no other medical conditions and no known cardiovascular risk factors.

Current and recent medications

• Lithium carbonate 600 mg twice daily (before his hospitalization he had been taking 600 mg twice daily; this was increased to 1,500 mg/day during the hospitalization and then decreased to the current dose as maintenance therapy)
• Divalproex (Depakote) 250 mg every night
• Gabapentin (Neurontin) 400 mg every night (the dosages of divalproex and gabapentin have remained unchanged since before his hospitalization)
• A multivitamin daily
• Naproxen (Naprosyn, Aleve) 250 mg up to two times a week for arthritic knee pain
• Aripiprazole (Abilify). This antipsychotic drug was recently discontinued because of parkinsonian symptoms, which then gradually improved.
• Memantine (Namenda), which is indicated for the treatment of moderate to severe Alzheimer disease. The patient reports that he stopped taking it after 3 weeks because he did not perceive it to be helping.

THE INITIAL EVALUATION

Physical examination

Temperature 98.3°F (36.8°C), pulse 60 beats per minute, respirations 16 per minute, blood pressure 126/64 mm Hg sitting and 118/71 mm Hg standing.

The patient is well groomed, alert, and cooperative. His head, eyes, ears, nose, and throat are normal. His teeth are in good condition. His skin is normal. We note no thyromegaly, carotid bruits, or palpable lymphadenopathy. His lungs are clear to auscultation. Results of cardiac, abdominal, and musculoskeletal examinations are all normal.

His deep tendon reflexes, sensory and motor testing, and gait are normal. The cerebellar examination is normal, aside from a mild tremor in his right hand when it is outstretched, with no resting tremor or cogwheel rigidity.

On the Mini-Mental State Examination (MMSE) he scores a perfect 30/30 (normal 24–30). He can draw a clock normally. His score on the short-form Geriatric Depression Scale is 4/15 (a score of 6 or higher indicates depression).

Laboratory tests

• Serum lithium level 0.8 mmol/L (therapeutic range 0.5–1.5 mmol/L) (his previous values are not available)
• Thyroid-stimulating hormone level 1.61 μU/mL (normal 0.40–5.50)
• Complete blood cell count and comprehensive metabolic panel values are within normal limits.

Magnetic resonance imaging

Noncontrast magnetic resonance imaging of the head reveals two nonspecific punctate foci of high signal intensity on T2-weighted images in the left frontal white matter, but the results are otherwise normal.

DIFFERENTIAL DIAGNOSIS

1. On the basis of this information, which is the most likely cause of this patient’s cogitive impairment?

• Dementia with Lewy bodies
• Early-onset Alzheimer disease
• Stroke with vascular cognitive impairment
• Lithium neurotoxicity

Lithium neurotoxicity is the most likely cause of this patient’s symptoms, given the temporal relationship between the adjusting of his lithium dose and the onset of his symptoms. Lithium therapy causes subtle cognitive deficits. Its dosing in older patients requires careful monitoring because of age-related alterations in its pharmacology and its various drug interactions; both mechanisms played a role in precipitating lithium toxicity in this patient.

Although his lithium levels are in the broadly accepted therapeutic range, there is much debate about the best maintenance level for patients with bipolar disorder. A level in the range of 1 to 1.2 mmol/L may be best in acute mania, while a lower level of around 0.8 mmol/L is preferred in the depressive phase. Once the patient’s mood has stabilized, the best maintenance level may be in the range of 0.2 to 0.6 mmol/L.

Dementia with Lewy bodies, although suggested by the patient’s cognitive impairment, history of parkinsonian symptoms, and somnolence, is an unlikely cause because his motor symptoms resolved after the aripiprazole was discontinued, his somnolence improved after the dose of lithium was reduced, and his alertness did not fluctuate thereafter as would be expected in dementia with Lewy bodies.

Alzheimer disease usually manifests as gradually progressive cognitive deficits involving memory impairment with one or more of the following: aphasia, apraxia, agnosia, and disturbance in executive functioning. In contrast, this patient’s memory loss was fairly abrupt and not slowly progressive.

Stroke is also unlikely, as he has no history of stroke or focal neurologic deficits. Although a magnetic resonance scan of the brain showed some evidence of small-vessel ischemic changes, it showed no cortical infarcts.

MECHANISMS OF LITHIUM NEUROTOXICITY

2. What are the possible mechanisms of lithium neurotoxicity in this patient?

• The increased dose of lithium
• The interaction of nonsteroidal anti-inflammatory drugs (NSAIDs) and lithium
• The interaction of the other psychotropic medications with lithium
• All of the above
• None of the above

All of the above could be contributing.

Although lithium is thought to cause side effects in as many as 60% of patients of any age who take it, the rate of serious adverse effects is reportedly higher in older patients than in younger patients.¹

That said, cognitive deficits are common in bipolar disorder irrespective of lithium use.

COGNITIVE IMPAIRMENT IN BIPOLAR DISORDER

3. If cognitive impairment in bipolar disorder is common, when does it occur?

• Only in the remission phase
• Only in the manic phase
• Only in the depression phase
• In all phases of the disease

Cognitive impairment occurs in all phases of bipolar disorder. Neuropsychological testing of bipolar patients in remission uncovers subtle, persistent cognitive impairment in executive function and in visuospatial memory without mood symptoms.^3–5 Impaired executive functioning, predominantly frontal lobe dysfunction, interferes with one’s ability to initiate, plan, perform, and successfully complete a task and challenges one’s ability to function effectively in society and to comply with medical advice and instructions on taking medications.

RECOMMENDATIONS

4. What should we recommend to this patient?

• Decrease the current dose of lithium
• Stop all medications
• Undergo detailed neuropsychological testing
• Follow up with a psychiatrist, if needed

The patient’s lithium level was within the therapeutic range and his bipolar symptoms were well controlled. In older patients, however, the optimal serum level of lithium is often unclear, making it advisable to reduce the dose when an adverse effect is suspected.

His other medications should be reviewed. Gabapentin is not indicated for use as a mood stabilizer, and his divalproex dose (250 mg) is well below the usual therapeutic dose of 1,000 to 2,000 mg/day.⁶ The gabapentin could be discontinued, and the divalproex could be increased to a therapeutic dose.

NSAIDs can increase serum lithium levels, diminish renal lithium clearance, and possibly induce lithium toxicity, but the effect varies considerably among drugs and individuals.⁷ We would advise this patient to stop taking naproxen and switch to acetaminophen (Tylenol) for his arthritis pain, and we would inform him of the risk of lithium toxicity with continuous use of NSAIDs.

We would also recommend additional neuropsychological testing. The patient noticed subtle difficulties in his cognitive abilities that were not apparent on the MMSE. While the MMSE is an acceptable cognitive test, it is often not sensitive enough to detect milder forms of cognitive impairment, especially in well-educated patients at the usual cut-point of 24. A comprehensive neuropsychological examination is a more sensitive measure of cognition, involving the detailed testing of various cognitive domains. It can reveal a pattern of cognitive impairment that helps to differentiate between normal and mood disorders and also can detect subtle executive dysfunction.

However, detailed neuropsychological testing is time-consuming and may not be obtained rapidly enough to help in making clinical decisions quickly. In this patient’s case, immediate collaboration and follow-up with the patient’s psychiatrist would be the most expeditious way to reassess the patient’s medication regimen.

FOLLOW-UP COURSE

We informed the patient’s psychiatrist that we thought the patient had increased sensitivity to lithium (even at “therapeutic” levels), possibly related to a drug-drug interaction.

His dose of lithium was kept at 600 mg twice daily, as the lithium toxicity was most likely due to a drug-drug interaction.

We discontinued his memantine, since he did not have Alzheimer disease and since he wasn’t taking it anyway. He continued taking gabapentin and divalproex at the same doses, and he stopped taking naproxyn and substituted acetaminophen for his arthritis pain. We advised him about about health maintenance, including proper nutrition, mineral and vitamin supplements, and exercise.

The patient underwent neuropsychological testing to better characterize his cognitive impairment. The findings did not suggest dementia, but were consistent with minor cognitive deficits caused by lithium.

When seen at a follow-up visit 6 weeks later the patient was free of symptoms except for the tremor in his dominant hand. His mood was stable and his cognition was better. No further changes were required in his psychotropic drug regimen.

TAKE-HOME POINTS

When a bipolar patient develops acute changes in cognition, we should suspect adverse effects of lithium as the cause, because of its narrow therapeutic window and interactions with other prescribed drugs. The case presented here reminds us to consider adverse drug effects any time an older patient develops acute changes in cognition. One should also consider the potential for a drug-drug interaction when reviewing the patient’s medication list and be especially vigilant in monitoring patients taking lithium, since its safety and effectiveness are affected by aging and by the co-administration of drugs that influence its clearance.

Despite these caveats, lithium remains an effective treatment in elderly patients, provided we are aware of the risks and benefits of its use.

A 61-year-old man presents for evaluation of new-onset cognitive impairment, which has developed over the past 6 to 8 months. He has bipolar disorder, for which he has been taking lithium carbonate (Eskalith) for the past 15 years. This therapy kept his mood stable until a relapse of depression and mania 1 year ago required hospitalization and an increase in the lithium dose, which was then lowered somewhat after he improved (see below). His cognitive symptoms appeared gradually within 2 months after his release from the hospital.

He now has difficulty concentrating, a tendency to substitute words incorrectly during conversation, and difficulty recalling names and “retrieving memories.” He also reports a worsening tremor in his dominant hand that compromises his ability to eat with a spoon or a fork. He complains of increasing daytime somnolence, which began when his lithium dose was increased and improved when the dose was decreased.

The patient is a mathematician and recently finished revising the curriculum for an undergraduate course in advanced mathematics that he teaches. He does not smoke cigarettes, and he drinks alcohol only socially. He has no other medical conditions and no known cardiovascular risk factors.

Current and recent medications

• Lithium carbonate 600 mg twice daily (before his hospitalization he had been taking 600 mg twice daily; this was increased to 1,500 mg/day during the hospitalization and then decreased to the current dose as maintenance therapy)
• Divalproex (Depakote) 250 mg every night
• Gabapentin (Neurontin) 400 mg every night (the dosages of divalproex and gabapentin have remained unchanged since before his hospitalization)
• A multivitamin daily
• Naproxen (Naprosyn, Aleve) 250 mg up to two times a week for arthritic knee pain
• Aripiprazole (Abilify). This antipsychotic drug was recently discontinued because of parkinsonian symptoms, which then gradually improved.
• Memantine (Namenda), which is indicated for the treatment of moderate to severe Alzheimer disease. The patient reports that he stopped taking it after 3 weeks because he did not perceive it to be helping.

THE INITIAL EVALUATION

Physical examination

Temperature 98.3°F (36.8°C), pulse 60 beats per minute, respirations 16 per minute, blood pressure 126/64 mm Hg sitting and 118/71 mm Hg standing.

The patient is well groomed, alert, and cooperative. His head, eyes, ears, nose, and throat are normal. His teeth are in good condition. His skin is normal. We note no thyromegaly, carotid bruits, or palpable lymphadenopathy. His lungs are clear to auscultation. Results of cardiac, abdominal, and musculoskeletal examinations are all normal.

His deep tendon reflexes, sensory and motor testing, and gait are normal. The cerebellar examination is normal, aside from a mild tremor in his right hand when it is outstretched, with no resting tremor or cogwheel rigidity.

On the Mini-Mental State Examination (MMSE) he scores a perfect 30/30 (normal 24–30). He can draw a clock normally. His score on the short-form Geriatric Depression Scale is 4/15 (a score of 6 or higher indicates depression).

Laboratory tests

• Serum lithium level 0.8 mmol/L (therapeutic range 0.5–1.5 mmol/L) (his previous values are not available)
• Thyroid-stimulating hormone level 1.61 μU/mL (normal 0.40–5.50)
• Complete blood cell count and comprehensive metabolic panel values are within normal limits.

Magnetic resonance imaging

Noncontrast magnetic resonance imaging of the head reveals two nonspecific punctate foci of high signal intensity on T2-weighted images in the left frontal white matter, but the results are otherwise normal.

DIFFERENTIAL DIAGNOSIS

1. On the basis of this information, which is the most likely cause of this patient’s cogitive impairment?

• Dementia with Lewy bodies
• Early-onset Alzheimer disease
• Stroke with vascular cognitive impairment
• Lithium neurotoxicity

Lithium neurotoxicity is the most likely cause of this patient’s symptoms, given the temporal relationship between the adjusting of his lithium dose and the onset of his symptoms. Lithium therapy causes subtle cognitive deficits. Its dosing in older patients requires careful monitoring because of age-related alterations in its pharmacology and its various drug interactions; both mechanisms played a role in precipitating lithium toxicity in this patient.

Although his lithium levels are in the broadly accepted therapeutic range, there is much debate about the best maintenance level for patients with bipolar disorder. A level in the range of 1 to 1.2 mmol/L may be best in acute mania, while a lower level of around 0.8 mmol/L is preferred in the depressive phase. Once the patient’s mood has stabilized, the best maintenance level may be in the range of 0.2 to 0.6 mmol/L.

Dementia with Lewy bodies, although suggested by the patient’s cognitive impairment, history of parkinsonian symptoms, and somnolence, is an unlikely cause because his motor symptoms resolved after the aripiprazole was discontinued, his somnolence improved after the dose of lithium was reduced, and his alertness did not fluctuate thereafter as would be expected in dementia with Lewy bodies.

Alzheimer disease usually manifests as gradually progressive cognitive deficits involving memory impairment with one or more of the following: aphasia, apraxia, agnosia, and disturbance in executive functioning. In contrast, this patient’s memory loss was fairly abrupt and not slowly progressive.

Stroke is also unlikely, as he has no history of stroke or focal neurologic deficits. Although a magnetic resonance scan of the brain showed some evidence of small-vessel ischemic changes, it showed no cortical infarcts.

MECHANISMS OF LITHIUM NEUROTOXICITY

2. What are the possible mechanisms of lithium neurotoxicity in this patient?

• The increased dose of lithium
• The interaction of nonsteroidal anti-inflammatory drugs (NSAIDs) and lithium
• The interaction of the other psychotropic medications with lithium
• All of the above
• None of the above

All of the above could be contributing.

Although lithium is thought to cause side effects in as many as 60% of patients of any age who take it, the rate of serious adverse effects is reportedly higher in older patients than in younger patients.¹

That said, cognitive deficits are common in bipolar disorder irrespective of lithium use.

COGNITIVE IMPAIRMENT IN BIPOLAR DISORDER

3. If cognitive impairment in bipolar disorder is common, when does it occur?

• Only in the remission phase
• Only in the manic phase
• Only in the depression phase
• In all phases of the disease

Cognitive impairment occurs in all phases of bipolar disorder. Neuropsychological testing of bipolar patients in remission uncovers subtle, persistent cognitive impairment in executive function and in visuospatial memory without mood symptoms.^3–5 Impaired executive functioning, predominantly frontal lobe dysfunction, interferes with one’s ability to initiate, plan, perform, and successfully complete a task and challenges one’s ability to function effectively in society and to comply with medical advice and instructions on taking medications.

RECOMMENDATIONS

4. What should we recommend to this patient?

• Decrease the current dose of lithium
• Stop all medications
• Undergo detailed neuropsychological testing
• Follow up with a psychiatrist, if needed

The patient’s lithium level was within the therapeutic range and his bipolar symptoms were well controlled. In older patients, however, the optimal serum level of lithium is often unclear, making it advisable to reduce the dose when an adverse effect is suspected.

His other medications should be reviewed. Gabapentin is not indicated for use as a mood stabilizer, and his divalproex dose (250 mg) is well below the usual therapeutic dose of 1,000 to 2,000 mg/day.⁶ The gabapentin could be discontinued, and the divalproex could be increased to a therapeutic dose.

NSAIDs can increase serum lithium levels, diminish renal lithium clearance, and possibly induce lithium toxicity, but the effect varies considerably among drugs and individuals.⁷ We would advise this patient to stop taking naproxen and switch to acetaminophen (Tylenol) for his arthritis pain, and we would inform him of the risk of lithium toxicity with continuous use of NSAIDs.

We would also recommend additional neuropsychological testing. The patient noticed subtle difficulties in his cognitive abilities that were not apparent on the MMSE. While the MMSE is an acceptable cognitive test, it is often not sensitive enough to detect milder forms of cognitive impairment, especially in well-educated patients at the usual cut-point of 24. A comprehensive neuropsychological examination is a more sensitive measure of cognition, involving the detailed testing of various cognitive domains. It can reveal a pattern of cognitive impairment that helps to differentiate between normal and mood disorders and also can detect subtle executive dysfunction.

However, detailed neuropsychological testing is time-consuming and may not be obtained rapidly enough to help in making clinical decisions quickly. In this patient’s case, immediate collaboration and follow-up with the patient’s psychiatrist would be the most expeditious way to reassess the patient’s medication regimen.

FOLLOW-UP COURSE

We informed the patient’s psychiatrist that we thought the patient had increased sensitivity to lithium (even at “therapeutic” levels), possibly related to a drug-drug interaction.

His dose of lithium was kept at 600 mg twice daily, as the lithium toxicity was most likely due to a drug-drug interaction.

We discontinued his memantine, since he did not have Alzheimer disease and since he wasn’t taking it anyway. He continued taking gabapentin and divalproex at the same doses, and he stopped taking naproxyn and substituted acetaminophen for his arthritis pain. We advised him about about health maintenance, including proper nutrition, mineral and vitamin supplements, and exercise.

The patient underwent neuropsychological testing to better characterize his cognitive impairment. The findings did not suggest dementia, but were consistent with minor cognitive deficits caused by lithium.

When seen at a follow-up visit 6 weeks later the patient was free of symptoms except for the tremor in his dominant hand. His mood was stable and his cognition was better. No further changes were required in his psychotropic drug regimen.

TAKE-HOME POINTS

When a bipolar patient develops acute changes in cognition, we should suspect adverse effects of lithium as the cause, because of its narrow therapeutic window and interactions with other prescribed drugs. The case presented here reminds us to consider adverse drug effects any time an older patient develops acute changes in cognition. One should also consider the potential for a drug-drug interaction when reviewing the patient’s medication list and be especially vigilant in monitoring patients taking lithium, since its safety and effectiveness are affected by aging and by the co-administration of drugs that influence its clearance.

Despite these caveats, lithium remains an effective treatment in elderly patients, provided we are aware of the risks and benefits of its use.

SAVANNAH, GA—Patients diagnosed with both anxiety disorder and autism spectrum disorder used almost tenfold more antipsychotic medications, and fewer SSRIs, than those diagnosed with anxiety disorder alone, reported Alya Reeve, MD, at the 19th Annual Meeting of the American Neuropsychiatric Association.

Dr. Reeve’s group determined the effect of autism spectrum disorder on medications prescribed for anxiety disorders. A retrospective review of 218 charts for nine years found that 98 patients (45%) had anxiety disorder; of these, 31 (32%) also had a diagnosis of autism spectrum disorder.

Additional comorbid psychiatric conditions included mood, impulse control, and attention disorders, as well as psychosis. Thirteen percent of those with anxiety disorder and autism spectrum disorder had mood disorder, compared with 51% of those without autism spectrum disorder. Rates for other psychiatric conditions were higher in the autism spectrum disorder group than in the non–autism spectrum disorder group for impulse control disorders (60% vs 46%, respectively) and attention disorders (6% vs 4%, respectively) and were the same for psychosis (13%). Thirty-five percent of those with anxiety disorder and autism spectrum disorder had hypothyroidism versus 23% of those without autism spectrum disorder; and 26% of those with anxiety disorder and autism spectrum disorder had seizures versus 33% of those without autism spectrum disorder. For patients with GERD, the rates were 16% versus 18%, respectively.

“Psychotropic medications and their indication for usage were derived from chart notes and forms,” said Dr. Reeve, an Associate Professor in the Department of Psychiatry at the University of New Mexico Health Sciences Center in Albuquerque. Psychotropic medications used for anxiety included SSRIs, antipsychotics, tricyclic antidepressants, and heterocyclics. Each medication was classified as “current use,” “used > 50% duration of service,” or “ever used.”

Despite similar psychotropic medication prescribing rates, 48% of patients with anxiety disorder and autism spectrum disorder were currently using an SSRI, compared with 70% of those without autism spectrum disorder. Conversely, 1.5% of patients without autism spectrum disorder were using an antipsychotic, compared with 13% of those with autism spectrum disorder.

Psychotropic medications prescribed but not used for anxiety included antipsychotics for psychotic symptoms such as impulse control, aggression, agitation, sleep, or self-injurious behaviors. These medications were used by 84% of patients with anxiety disorder and autism spectrum disorder, compared with 69% of those without autism spectrum disorder. Other psychotropics, such as antiepileptics, anxiolytics, antidepressants, sedatives, and antihypertensives prescribed for impulse control, sleep attention, agitation, aggression, or self-injurious behaviors, were used by more patients with anxiety disorder and autism spectrum disorder than those without (87% vs 63%, respectively). Medications used as needed (eg, for anxiety prior to a dentist visit) or for nonanxiety symptoms (eg, trazodone for sleep) were excluded.

“Patients with autism spectrum disorder used SSRIs less successfully, and antipsychotics more successfully, than those without autism spectrum disorder,” Dr. Reeve concluded. “This may reflect a population with higher behavior challenges compounding anxiety disorder.”

SAVANNAH, GA—Patients diagnosed with both anxiety disorder and autism spectrum disorder used almost tenfold more antipsychotic medications, and fewer SSRIs, than those diagnosed with anxiety disorder alone, reported Alya Reeve, MD, at the 19th Annual Meeting of the American Neuropsychiatric Association.

Dr. Reeve’s group determined the effect of autism spectrum disorder on medications prescribed for anxiety disorders. A retrospective review of 218 charts for nine years found that 98 patients (45%) had anxiety disorder; of these, 31 (32%) also had a diagnosis of autism spectrum disorder.

Additional comorbid psychiatric conditions included mood, impulse control, and attention disorders, as well as psychosis. Thirteen percent of those with anxiety disorder and autism spectrum disorder had mood disorder, compared with 51% of those without autism spectrum disorder. Rates for other psychiatric conditions were higher in the autism spectrum disorder group than in the non–autism spectrum disorder group for impulse control disorders (60% vs 46%, respectively) and attention disorders (6% vs 4%, respectively) and were the same for psychosis (13%). Thirty-five percent of those with anxiety disorder and autism spectrum disorder had hypothyroidism versus 23% of those without autism spectrum disorder; and 26% of those with anxiety disorder and autism spectrum disorder had seizures versus 33% of those without autism spectrum disorder. For patients with GERD, the rates were 16% versus 18%, respectively.

“Psychotropic medications and their indication for usage were derived from chart notes and forms,” said Dr. Reeve, an Associate Professor in the Department of Psychiatry at the University of New Mexico Health Sciences Center in Albuquerque. Psychotropic medications used for anxiety included SSRIs, antipsychotics, tricyclic antidepressants, and heterocyclics. Each medication was classified as “current use,” “used > 50% duration of service,” or “ever used.”

Despite similar psychotropic medication prescribing rates, 48% of patients with anxiety disorder and autism spectrum disorder were currently using an SSRI, compared with 70% of those without autism spectrum disorder. Conversely, 1.5% of patients without autism spectrum disorder were using an antipsychotic, compared with 13% of those with autism spectrum disorder.

Psychotropic medications prescribed but not used for anxiety included antipsychotics for psychotic symptoms such as impulse control, aggression, agitation, sleep, or self-injurious behaviors. These medications were used by 84% of patients with anxiety disorder and autism spectrum disorder, compared with 69% of those without autism spectrum disorder. Other psychotropics, such as antiepileptics, anxiolytics, antidepressants, sedatives, and antihypertensives prescribed for impulse control, sleep attention, agitation, aggression, or self-injurious behaviors, were used by more patients with anxiety disorder and autism spectrum disorder than those without (87% vs 63%, respectively). Medications used as needed (eg, for anxiety prior to a dentist visit) or for nonanxiety symptoms (eg, trazodone for sleep) were excluded.

“Patients with autism spectrum disorder used SSRIs less successfully, and antipsychotics more successfully, than those without autism spectrum disorder,” Dr. Reeve concluded. “This may reflect a population with higher behavior challenges compounding anxiety disorder.”

SAVANNAH, GA—Patients diagnosed with both anxiety disorder and autism spectrum disorder used almost tenfold more antipsychotic medications, and fewer SSRIs, than those diagnosed with anxiety disorder alone, reported Alya Reeve, MD, at the 19th Annual Meeting of the American Neuropsychiatric Association.

Dr. Reeve’s group determined the effect of autism spectrum disorder on medications prescribed for anxiety disorders. A retrospective review of 218 charts for nine years found that 98 patients (45%) had anxiety disorder; of these, 31 (32%) also had a diagnosis of autism spectrum disorder.

Additional comorbid psychiatric conditions included mood, impulse control, and attention disorders, as well as psychosis. Thirteen percent of those with anxiety disorder and autism spectrum disorder had mood disorder, compared with 51% of those without autism spectrum disorder. Rates for other psychiatric conditions were higher in the autism spectrum disorder group than in the non–autism spectrum disorder group for impulse control disorders (60% vs 46%, respectively) and attention disorders (6% vs 4%, respectively) and were the same for psychosis (13%). Thirty-five percent of those with anxiety disorder and autism spectrum disorder had hypothyroidism versus 23% of those without autism spectrum disorder; and 26% of those with anxiety disorder and autism spectrum disorder had seizures versus 33% of those without autism spectrum disorder. For patients with GERD, the rates were 16% versus 18%, respectively.

“Psychotropic medications and their indication for usage were derived from chart notes and forms,” said Dr. Reeve, an Associate Professor in the Department of Psychiatry at the University of New Mexico Health Sciences Center in Albuquerque. Psychotropic medications used for anxiety included SSRIs, antipsychotics, tricyclic antidepressants, and heterocyclics. Each medication was classified as “current use,” “used > 50% duration of service,” or “ever used.”

Despite similar psychotropic medication prescribing rates, 48% of patients with anxiety disorder and autism spectrum disorder were currently using an SSRI, compared with 70% of those without autism spectrum disorder. Conversely, 1.5% of patients without autism spectrum disorder were using an antipsychotic, compared with 13% of those with autism spectrum disorder.

Psychotropic medications prescribed but not used for anxiety included antipsychotics for psychotic symptoms such as impulse control, aggression, agitation, sleep, or self-injurious behaviors. These medications were used by 84% of patients with anxiety disorder and autism spectrum disorder, compared with 69% of those without autism spectrum disorder. Other psychotropics, such as antiepileptics, anxiolytics, antidepressants, sedatives, and antihypertensives prescribed for impulse control, sleep attention, agitation, aggression, or self-injurious behaviors, were used by more patients with anxiety disorder and autism spectrum disorder than those without (87% vs 63%, respectively). Medications used as needed (eg, for anxiety prior to a dentist visit) or for nonanxiety symptoms (eg, trazodone for sleep) were excluded.

“Patients with autism spectrum disorder used SSRIs less successfully, and antipsychotics more successfully, than those without autism spectrum disorder,” Dr. Reeve concluded. “This may reflect a population with higher behavior challenges compounding anxiety disorder.”

ILLUSTRATIVE CASE

A 52-year-old man presents to your office for follow-up 2 days after he was seen in the ED and diagnosed with a distal ureteral calculus, his first. His pain is reasonably well controlled, but he has not yet passed the stone. Is there anything you can do to help him pass the stone?

Yes. Patients who are candidates for observation should be offered a trial of “medical expulsive therapy” using an α-antagonist or a calcium channel blocker. Until now, medical therapy for kidney stones consisted of pain relief only.

The ordeal of a first stone is all too common—the lifetime prevalence of kidney stones is 5.2%—and the probability of recurrence is about 50%.^2,3

NHANES data show increasing prevalence between the periods 1976-1980 and 1988-1996.³ One fifth to one third of kidney stones require surgical intervention.⁴ In a cohort of 245 patients presenting to an ED in Canada, 50 (20%) required further procedures, including lithotripsy. Stones ≥ 6 mm in size were much less likely to pass (OR=10.7, 95% CI 4.6-24.8).⁵ The burden on the healthcare system is significant; there are approximately 2 million out-patient visits annually for this problem, and diagnosis and treatment costs about $2 billion annually.⁶

Watch and wait

The standard approach is a period of watchful waiting and pain control, with urgent urological referral for patients with evidence of upper urinary tract infection, high grade obstruction, inadequate pain or nausea control, or insufficient renal reserve.^2,4 Most patients treated with watchful waiting pass their stone within 4 weeks. Any stones that don’t pass within 8 weeks are unlikely to pass spontaneously.^2,7

Medical therapy has been proposed for decades

Medications that relax ureteral smooth muscle to help pass ureteral stones have been proposed for decades.⁸ Prior to 2000, however, only 1 randomized controlled trial (RCT) of medical therapy for ureteral stones had been published.⁹ A subsequent meta-analysis found 9 studies and showed that medical therapy did increase the chances that a stone would pass.¹⁰ The Singh meta-analysis found 13 subsequently published studies and nearly tripled the number of patients evaluated.

STUDY SUMMARY: A well-done meta-analysis

This meta-analysis is based on 16 studies of α-antagonists (most used tamsulosin) and 9 studies of nifedipine, a calcium channel blocker.¹ The studies were identified by a comprehensive search strategy that included Medline, EMBASE, and the Cochrane Controlled Trials Register from January 1980 to January 2007. The authors included all randomized trials or controlled clinical trials of medical therapy for adults with acute ureteral colic.

The authors assessed the studies for quality using the Jadad scale, a validated scale of study quality. Higher scores represent better quality, including better documentation of randomization, blinding, and follow-up. The authors specified their planned sensitivity analyses, and used the random effects model to synthesize the results, which tends to provide a more conservative estimate of the effect.

In other words, this was a very well done meta-analysis.

Twenty-two studies met the inclusion criteria: 13 of α-antagonists, 6 of nifedipine, and 3 of both. In 13 of the 16 studies of α-antagonists, tamsulosin (Flomax) was the study drug. The results from the terazosin (Hytrin) and doxazosin (Cardura) studies were included with the tamsulosin studies. The Jadad quality scores of the 22 studies were fairly low, with a median of 2 (range of 0 to 3) on the 5-point scale. The most common deduction was because the study was not double-blinded.

Medical therapy makes sense

α-Antagonist studies

These 16 studies enrolled 1235 patients with distal ureteral stones. Mean stone size ranged from 4.3 to 7.8 mm. α-Antagonists improved the stone expulsion rate (RR= 1.59, 95% CI 1.44-1.75; NNT=3.3).

The mean time to expulsion of the stone ranged from 2.7 to 14.2 days and duration of therapy ranged from 1 to 7 weeks. In the 9 trials that reported the time to stone expulsion, the stone came out between 2 and 6 days earlier than the control groups.

Adverse effects were reported in 4% of patients receiving the active medication; most were mild.

Nifedipine studies

There were 686 patients in the 9 trials of nifedipine. The mean stone size was 3.9 to 12.8 mm. Some studies included stones in the more proximal as well as the distal ureter.

Nifedipine treatment increased the rate of stone expulsion (RR=1.5, 95% CI 1.34-1.68; NNT=3.9). Time to stone expulsion was shorter in 7 of the 9 studies.

Adverse effects were reported in 15% of the patients. Most of these were mild— nausea, vomiting, asthenia, and dyspepsia.

WHAT’S NEW: Strong evidence for use of medical therapy

The new findings from the Singh meta-analysis reviewed in this PURL supports physicians who have already adopted this practice and should encourage usage by those who have not yet done so.

Inpatients in academic medical centers

There is a growing trend to use tamsulosin to facilitate passage of ureteral stones. The University Health System Consortium (www.uhc.org) has complete clinical data on inpatients with ureteral stones, from 64 academic medical centers and teaching hospitals, between 2003 and 2007. We used this database to analyze trends in the use of tamsulosin in 4300 inpatients with ureteral stones (ICD 9 code 5921).

In 2003, only 3.3% of patients with a discharge diagnosis of ureteral stone received tamsulosin. In 2007, 34.1% of patients with ureteral stones discharged from these hospitals received tamsulosin, with similar rates of use when stratified by the specialty of the attending physician at discharge (family medicine, emergency medicine, internal medicine, urology) (FIGURE 1). We noted a wide range in the rate of adoption of this practice among academic medical centers: 48% in the centers with the highest rate of usage and 4.4% in the centers with the lowest rate.

FIGURE 1
% of inpatients in academic medical centers who received tamsulosin for ureteral stones, by year

Outpatients from a sample of US practices

The use of tamsulosin or nifedipine in outpatient practice was infrequent even 2 or 3 years ago. We used the National Ambulatory Medical Care Survey data (www.cdc.gov/nchs/about/major/ahcd/ahcd1.htm) from 2004 and 2005 (the most recent available), which provides a sample of all US outpatient practices. Only 7% of an estimated 1,345,000 patients diagnosed with ureteral stones were prescribed either tamsulosin or nifedipine, and urologists cared for most of those.

These unpublished data show that physicians in academic medical centers are increasingly adopting the practice of using tamsulosin or nifedipine for expulsion of ureteral stones, that urologists appear to be the first to begin using these medications in outpatients several years ago, and that this practice is being adopted actively in selected academic medical centers.

CAVEATS: Is either drug better? Too little data to tell

Our conclusion is that the strengths of this meta-analysis outweigh the weaknesses, the findings across studies are consistent, and the use of smooth-muscle relaxants for this indication makes sense from a mechanistic point of view.

The quality of a meta-analysis is only as good as the quality of the included studies, and, in this case, the overall quality of studies was not uniformly high. Median Jadad score, a summary measure of study quality, was 2, and the highest score was 3 (of a maximum of 5). The most common problem was lack of blinding, which can be critical in studies with subjective outcomes such as pain. We doubt that the lack of blinding led to any significant misclassification of outcome in this study, however.

Patients either passed the stone or they didn’t, or had a surgical intervention or not. It is reassuring that, when the best quality studies (Jadad score= 3) were analyzed separately, the results were equally good.

There have not been sufficient head-to-head trials to know if one is better than the other. We prefer α-antagonists because of the lower apparent side-effect profile. Our analysis of the UHC data shows that most of the physicians who are using medical therapy are using tamsulosin primarily for this diagnosis.

The majority of the patients in the studies included in the meta-analysis had been referred to a urologist. This raises the possibility that this treatment may not be as effective in patients with less severe symptoms for whom urological consultation is not necessary.

CHALLENGES TO IMPLEMENTATION: This change should be easy to put into practice

Tamsulosin is the best studied of the drugs, but also the most expensive. Based on the estimated number need to treat (NNT) of between 3 and 4 to prevent a surgical intervention and an estimated cost of around $90 for 1 month (www. drugstore.com, February 16, 2008), tamsulosin seems like a good investment to avoid surgical intervention.

The evidence for the other α-antagonists is consistent with that of tamsulosin, but there are fewer data, so it is not clear that the other agents will work as well.

Many people with renal colic are diagnosed and treated in the emergency department; they may not see their family physician until some time after the stone is diagnosed. It is unclear what effect this delay might have on medication effectiveness.

Neither tamsulosin nor nifedipine have an FDA indication for ureterolithiasis. However, they are prescribed commonly, and most physicians are familiar with their use and adverse-effect profiles.

Drugs used in the meta-analysis studies

α-Antagonists

Tamsulosin (Flomax)
Terazosin (Hytrin)
Doxazosin (Cardura)

Calcium channel blockers

Nifedipine (Adalat, Nifedical, Procardia)

Acknowledgement

We acknowledge Sofia Medvedev, PhD of the University HealthSystem Consortium (UHC) in Oak Brook, IL for analysis of the UHC Clinical Database and the National Ambulatory Medical Care Survey data.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 52-year-old man presents to your office for follow-up 2 days after he was seen in the ED and diagnosed with a distal ureteral calculus, his first. His pain is reasonably well controlled, but he has not yet passed the stone. Is there anything you can do to help him pass the stone?

Yes. Patients who are candidates for observation should be offered a trial of “medical expulsive therapy” using an α-antagonist or a calcium channel blocker. Until now, medical therapy for kidney stones consisted of pain relief only.

The ordeal of a first stone is all too common—the lifetime prevalence of kidney stones is 5.2%—and the probability of recurrence is about 50%.^2,3

NHANES data show increasing prevalence between the periods 1976-1980 and 1988-1996.³ One fifth to one third of kidney stones require surgical intervention.⁴ In a cohort of 245 patients presenting to an ED in Canada, 50 (20%) required further procedures, including lithotripsy. Stones ≥ 6 mm in size were much less likely to pass (OR=10.7, 95% CI 4.6-24.8).⁵ The burden on the healthcare system is significant; there are approximately 2 million out-patient visits annually for this problem, and diagnosis and treatment costs about $2 billion annually.⁶

Watch and wait

The standard approach is a period of watchful waiting and pain control, with urgent urological referral for patients with evidence of upper urinary tract infection, high grade obstruction, inadequate pain or nausea control, or insufficient renal reserve.^2,4 Most patients treated with watchful waiting pass their stone within 4 weeks. Any stones that don’t pass within 8 weeks are unlikely to pass spontaneously.^2,7

Medical therapy has been proposed for decades

Medications that relax ureteral smooth muscle to help pass ureteral stones have been proposed for decades.⁸ Prior to 2000, however, only 1 randomized controlled trial (RCT) of medical therapy for ureteral stones had been published.⁹ A subsequent meta-analysis found 9 studies and showed that medical therapy did increase the chances that a stone would pass.¹⁰ The Singh meta-analysis found 13 subsequently published studies and nearly tripled the number of patients evaluated.

STUDY SUMMARY: A well-done meta-analysis

This meta-analysis is based on 16 studies of α-antagonists (most used tamsulosin) and 9 studies of nifedipine, a calcium channel blocker.¹ The studies were identified by a comprehensive search strategy that included Medline, EMBASE, and the Cochrane Controlled Trials Register from January 1980 to January 2007. The authors included all randomized trials or controlled clinical trials of medical therapy for adults with acute ureteral colic.

The authors assessed the studies for quality using the Jadad scale, a validated scale of study quality. Higher scores represent better quality, including better documentation of randomization, blinding, and follow-up. The authors specified their planned sensitivity analyses, and used the random effects model to synthesize the results, which tends to provide a more conservative estimate of the effect.

In other words, this was a very well done meta-analysis.

Twenty-two studies met the inclusion criteria: 13 of α-antagonists, 6 of nifedipine, and 3 of both. In 13 of the 16 studies of α-antagonists, tamsulosin (Flomax) was the study drug. The results from the terazosin (Hytrin) and doxazosin (Cardura) studies were included with the tamsulosin studies. The Jadad quality scores of the 22 studies were fairly low, with a median of 2 (range of 0 to 3) on the 5-point scale. The most common deduction was because the study was not double-blinded.

Medical therapy makes sense

α-Antagonist studies

These 16 studies enrolled 1235 patients with distal ureteral stones. Mean stone size ranged from 4.3 to 7.8 mm. α-Antagonists improved the stone expulsion rate (RR= 1.59, 95% CI 1.44-1.75; NNT=3.3).

The mean time to expulsion of the stone ranged from 2.7 to 14.2 days and duration of therapy ranged from 1 to 7 weeks. In the 9 trials that reported the time to stone expulsion, the stone came out between 2 and 6 days earlier than the control groups.

Adverse effects were reported in 4% of patients receiving the active medication; most were mild.

Nifedipine studies

There were 686 patients in the 9 trials of nifedipine. The mean stone size was 3.9 to 12.8 mm. Some studies included stones in the more proximal as well as the distal ureter.

Nifedipine treatment increased the rate of stone expulsion (RR=1.5, 95% CI 1.34-1.68; NNT=3.9). Time to stone expulsion was shorter in 7 of the 9 studies.

Adverse effects were reported in 15% of the patients. Most of these were mild— nausea, vomiting, asthenia, and dyspepsia.

WHAT’S NEW: Strong evidence for use of medical therapy

The new findings from the Singh meta-analysis reviewed in this PURL supports physicians who have already adopted this practice and should encourage usage by those who have not yet done so.

Inpatients in academic medical centers

There is a growing trend to use tamsulosin to facilitate passage of ureteral stones. The University Health System Consortium (www.uhc.org) has complete clinical data on inpatients with ureteral stones, from 64 academic medical centers and teaching hospitals, between 2003 and 2007. We used this database to analyze trends in the use of tamsulosin in 4300 inpatients with ureteral stones (ICD 9 code 5921).

In 2003, only 3.3% of patients with a discharge diagnosis of ureteral stone received tamsulosin. In 2007, 34.1% of patients with ureteral stones discharged from these hospitals received tamsulosin, with similar rates of use when stratified by the specialty of the attending physician at discharge (family medicine, emergency medicine, internal medicine, urology) (FIGURE 1). We noted a wide range in the rate of adoption of this practice among academic medical centers: 48% in the centers with the highest rate of usage and 4.4% in the centers with the lowest rate.

FIGURE 1
% of inpatients in academic medical centers who received tamsulosin for ureteral stones, by year

Outpatients from a sample of US practices

The use of tamsulosin or nifedipine in outpatient practice was infrequent even 2 or 3 years ago. We used the National Ambulatory Medical Care Survey data (www.cdc.gov/nchs/about/major/ahcd/ahcd1.htm) from 2004 and 2005 (the most recent available), which provides a sample of all US outpatient practices. Only 7% of an estimated 1,345,000 patients diagnosed with ureteral stones were prescribed either tamsulosin or nifedipine, and urologists cared for most of those.

These unpublished data show that physicians in academic medical centers are increasingly adopting the practice of using tamsulosin or nifedipine for expulsion of ureteral stones, that urologists appear to be the first to begin using these medications in outpatients several years ago, and that this practice is being adopted actively in selected academic medical centers.

CAVEATS: Is either drug better? Too little data to tell

Our conclusion is that the strengths of this meta-analysis outweigh the weaknesses, the findings across studies are consistent, and the use of smooth-muscle relaxants for this indication makes sense from a mechanistic point of view.

The quality of a meta-analysis is only as good as the quality of the included studies, and, in this case, the overall quality of studies was not uniformly high. Median Jadad score, a summary measure of study quality, was 2, and the highest score was 3 (of a maximum of 5). The most common problem was lack of blinding, which can be critical in studies with subjective outcomes such as pain. We doubt that the lack of blinding led to any significant misclassification of outcome in this study, however.

Patients either passed the stone or they didn’t, or had a surgical intervention or not. It is reassuring that, when the best quality studies (Jadad score= 3) were analyzed separately, the results were equally good.

There have not been sufficient head-to-head trials to know if one is better than the other. We prefer α-antagonists because of the lower apparent side-effect profile. Our analysis of the UHC data shows that most of the physicians who are using medical therapy are using tamsulosin primarily for this diagnosis.

The majority of the patients in the studies included in the meta-analysis had been referred to a urologist. This raises the possibility that this treatment may not be as effective in patients with less severe symptoms for whom urological consultation is not necessary.

CHALLENGES TO IMPLEMENTATION: This change should be easy to put into practice

Tamsulosin is the best studied of the drugs, but also the most expensive. Based on the estimated number need to treat (NNT) of between 3 and 4 to prevent a surgical intervention and an estimated cost of around $90 for 1 month (www. drugstore.com, February 16, 2008), tamsulosin seems like a good investment to avoid surgical intervention.

The evidence for the other α-antagonists is consistent with that of tamsulosin, but there are fewer data, so it is not clear that the other agents will work as well.

Many people with renal colic are diagnosed and treated in the emergency department; they may not see their family physician until some time after the stone is diagnosed. It is unclear what effect this delay might have on medication effectiveness.

Neither tamsulosin nor nifedipine have an FDA indication for ureterolithiasis. However, they are prescribed commonly, and most physicians are familiar with their use and adverse-effect profiles.

Drugs used in the meta-analysis studies

α-Antagonists

Tamsulosin (Flomax)
Terazosin (Hytrin)
Doxazosin (Cardura)

Calcium channel blockers

Nifedipine (Adalat, Nifedical, Procardia)

Acknowledgement

We acknowledge Sofia Medvedev, PhD of the University HealthSystem Consortium (UHC) in Oak Brook, IL for analysis of the UHC Clinical Database and the National Ambulatory Medical Care Survey data.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 52-year-old man presents to your office for follow-up 2 days after he was seen in the ED and diagnosed with a distal ureteral calculus, his first. His pain is reasonably well controlled, but he has not yet passed the stone. Is there anything you can do to help him pass the stone?

Yes. Patients who are candidates for observation should be offered a trial of “medical expulsive therapy” using an α-antagonist or a calcium channel blocker. Until now, medical therapy for kidney stones consisted of pain relief only.

The ordeal of a first stone is all too common—the lifetime prevalence of kidney stones is 5.2%—and the probability of recurrence is about 50%.^2,3

NHANES data show increasing prevalence between the periods 1976-1980 and 1988-1996.³ One fifth to one third of kidney stones require surgical intervention.⁴ In a cohort of 245 patients presenting to an ED in Canada, 50 (20%) required further procedures, including lithotripsy. Stones ≥ 6 mm in size were much less likely to pass (OR=10.7, 95% CI 4.6-24.8).⁵ The burden on the healthcare system is significant; there are approximately 2 million out-patient visits annually for this problem, and diagnosis and treatment costs about $2 billion annually.⁶

Watch and wait

The standard approach is a period of watchful waiting and pain control, with urgent urological referral for patients with evidence of upper urinary tract infection, high grade obstruction, inadequate pain or nausea control, or insufficient renal reserve.^2,4 Most patients treated with watchful waiting pass their stone within 4 weeks. Any stones that don’t pass within 8 weeks are unlikely to pass spontaneously.^2,7

Medical therapy has been proposed for decades

Medications that relax ureteral smooth muscle to help pass ureteral stones have been proposed for decades.⁸ Prior to 2000, however, only 1 randomized controlled trial (RCT) of medical therapy for ureteral stones had been published.⁹ A subsequent meta-analysis found 9 studies and showed that medical therapy did increase the chances that a stone would pass.¹⁰ The Singh meta-analysis found 13 subsequently published studies and nearly tripled the number of patients evaluated.

STUDY SUMMARY: A well-done meta-analysis

This meta-analysis is based on 16 studies of α-antagonists (most used tamsulosin) and 9 studies of nifedipine, a calcium channel blocker.¹ The studies were identified by a comprehensive search strategy that included Medline, EMBASE, and the Cochrane Controlled Trials Register from January 1980 to January 2007. The authors included all randomized trials or controlled clinical trials of medical therapy for adults with acute ureteral colic.

The authors assessed the studies for quality using the Jadad scale, a validated scale of study quality. Higher scores represent better quality, including better documentation of randomization, blinding, and follow-up. The authors specified their planned sensitivity analyses, and used the random effects model to synthesize the results, which tends to provide a more conservative estimate of the effect.

In other words, this was a very well done meta-analysis.

Twenty-two studies met the inclusion criteria: 13 of α-antagonists, 6 of nifedipine, and 3 of both. In 13 of the 16 studies of α-antagonists, tamsulosin (Flomax) was the study drug. The results from the terazosin (Hytrin) and doxazosin (Cardura) studies were included with the tamsulosin studies. The Jadad quality scores of the 22 studies were fairly low, with a median of 2 (range of 0 to 3) on the 5-point scale. The most common deduction was because the study was not double-blinded.

Medical therapy makes sense

α-Antagonist studies

These 16 studies enrolled 1235 patients with distal ureteral stones. Mean stone size ranged from 4.3 to 7.8 mm. α-Antagonists improved the stone expulsion rate (RR= 1.59, 95% CI 1.44-1.75; NNT=3.3).

The mean time to expulsion of the stone ranged from 2.7 to 14.2 days and duration of therapy ranged from 1 to 7 weeks. In the 9 trials that reported the time to stone expulsion, the stone came out between 2 and 6 days earlier than the control groups.

Adverse effects were reported in 4% of patients receiving the active medication; most were mild.

Nifedipine studies

There were 686 patients in the 9 trials of nifedipine. The mean stone size was 3.9 to 12.8 mm. Some studies included stones in the more proximal as well as the distal ureter.

Nifedipine treatment increased the rate of stone expulsion (RR=1.5, 95% CI 1.34-1.68; NNT=3.9). Time to stone expulsion was shorter in 7 of the 9 studies.

Adverse effects were reported in 15% of the patients. Most of these were mild— nausea, vomiting, asthenia, and dyspepsia.

WHAT’S NEW: Strong evidence for use of medical therapy

The new findings from the Singh meta-analysis reviewed in this PURL supports physicians who have already adopted this practice and should encourage usage by those who have not yet done so.

Inpatients in academic medical centers

There is a growing trend to use tamsulosin to facilitate passage of ureteral stones. The University Health System Consortium (www.uhc.org) has complete clinical data on inpatients with ureteral stones, from 64 academic medical centers and teaching hospitals, between 2003 and 2007. We used this database to analyze trends in the use of tamsulosin in 4300 inpatients with ureteral stones (ICD 9 code 5921).

In 2003, only 3.3% of patients with a discharge diagnosis of ureteral stone received tamsulosin. In 2007, 34.1% of patients with ureteral stones discharged from these hospitals received tamsulosin, with similar rates of use when stratified by the specialty of the attending physician at discharge (family medicine, emergency medicine, internal medicine, urology) (FIGURE 1). We noted a wide range in the rate of adoption of this practice among academic medical centers: 48% in the centers with the highest rate of usage and 4.4% in the centers with the lowest rate.

FIGURE 1
% of inpatients in academic medical centers who received tamsulosin for ureteral stones, by year

Outpatients from a sample of US practices

The use of tamsulosin or nifedipine in outpatient practice was infrequent even 2 or 3 years ago. We used the National Ambulatory Medical Care Survey data (www.cdc.gov/nchs/about/major/ahcd/ahcd1.htm) from 2004 and 2005 (the most recent available), which provides a sample of all US outpatient practices. Only 7% of an estimated 1,345,000 patients diagnosed with ureteral stones were prescribed either tamsulosin or nifedipine, and urologists cared for most of those.

These unpublished data show that physicians in academic medical centers are increasingly adopting the practice of using tamsulosin or nifedipine for expulsion of ureteral stones, that urologists appear to be the first to begin using these medications in outpatients several years ago, and that this practice is being adopted actively in selected academic medical centers.

CAVEATS: Is either drug better? Too little data to tell

Our conclusion is that the strengths of this meta-analysis outweigh the weaknesses, the findings across studies are consistent, and the use of smooth-muscle relaxants for this indication makes sense from a mechanistic point of view.

The quality of a meta-analysis is only as good as the quality of the included studies, and, in this case, the overall quality of studies was not uniformly high. Median Jadad score, a summary measure of study quality, was 2, and the highest score was 3 (of a maximum of 5). The most common problem was lack of blinding, which can be critical in studies with subjective outcomes such as pain. We doubt that the lack of blinding led to any significant misclassification of outcome in this study, however.

Patients either passed the stone or they didn’t, or had a surgical intervention or not. It is reassuring that, when the best quality studies (Jadad score= 3) were analyzed separately, the results were equally good.

There have not been sufficient head-to-head trials to know if one is better than the other. We prefer α-antagonists because of the lower apparent side-effect profile. Our analysis of the UHC data shows that most of the physicians who are using medical therapy are using tamsulosin primarily for this diagnosis.

The majority of the patients in the studies included in the meta-analysis had been referred to a urologist. This raises the possibility that this treatment may not be as effective in patients with less severe symptoms for whom urological consultation is not necessary.

CHALLENGES TO IMPLEMENTATION: This change should be easy to put into practice

Tamsulosin is the best studied of the drugs, but also the most expensive. Based on the estimated number need to treat (NNT) of between 3 and 4 to prevent a surgical intervention and an estimated cost of around $90 for 1 month (www. drugstore.com, February 16, 2008), tamsulosin seems like a good investment to avoid surgical intervention.

The evidence for the other α-antagonists is consistent with that of tamsulosin, but there are fewer data, so it is not clear that the other agents will work as well.

Many people with renal colic are diagnosed and treated in the emergency department; they may not see their family physician until some time after the stone is diagnosed. It is unclear what effect this delay might have on medication effectiveness.

Neither tamsulosin nor nifedipine have an FDA indication for ureterolithiasis. However, they are prescribed commonly, and most physicians are familiar with their use and adverse-effect profiles.

Drugs used in the meta-analysis studies

α-Antagonists

Tamsulosin (Flomax)
Terazosin (Hytrin)
Doxazosin (Cardura)

Calcium channel blockers

Nifedipine (Adalat, Nifedical, Procardia)

Acknowledgement

We acknowledge Sofia Medvedev, PhD of the University HealthSystem Consortium (UHC) in Oak Brook, IL for analysis of the UHC Clinical Database and the National Ambulatory Medical Care Survey data.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

Measles is still a threat. Endemic transmission of measles no longer occurs in the United States (or any of the Americas), yet this highly infectious disease is still a threat from importation by visitors from other countries and from US residents who have traveled abroad. Two recent outbreaks (described at left) illustrate these risks.

What the CDC discovered

The 2 outbreaks of import-linked measles brought home—literally—the sobering facts about vulnerability among US residents. The CDC report ^1,2 of its investigation observed:

US travelers can be exposed almost anywhere, developed countries included. The California outbreak started with a visit to Switzerland.

Measles spreads rapidly in susceptible subgroups, unless effective control strategies are used. In California, on 2 consecutive days, 5 school children and 4 children in a doctor’s office were infected; all were unvaccinated.

People not considered at risk can contract measles. Although 2 doses of vaccine are 99% effective, vaccinated individuals, such as the college students, can contract measles. Likewise, people born before 1957 may not be immune, in contrast to the general definition of immunity (see Measles Basics. Case in point: the airline passenger, born in 1954.

Disease can be severe. The 40-year-old salesperson (no documented vaccination) was hospitalized with seizure, 105ºF fever, and pneumonia. One of the infants was hospitalized due to dehydration.

People in routine contact with travelers entering the United States can be exposed to measles—like the airline worker.

Take-home lessons for family physicians

Include measles in the differential diagnosis of patients who have fever and rash, especially if they have traveled to another country within the past 3 to 4 weeks. Any patient who meets the definition of measles (fever 101ºF or higher; rash; and at least 1 of the 3 Cs—cough, coryza, conjunctivitis) should be immediately reported to the local health department. The health department will provide instructions for collecting laboratory samples for confirmation; instructions on patient isolation; and assistance with notification and disease control measures for exposed individuals.

Immunize patients and staff. These recurring cases of imported measles underscore the importance of maintaining a high level of immunity. Outbreaks can happen even where immunity is 90% to 95%. When vaccination rates dip below 90%, sustained outbreaks can occur.⁶

Ensure that staff and patients are all immunized against vaccine-preventable diseases, and inform concerned parents about the safety and effectiveness of vaccines. Parents who refuse to have their children vaccinated place their children at risk and contribute to higher community risk. Communities that have higher rates of non-adherence to vaccine recommendations are more likely to have outbreaks.^7,8

Use strict infection control in the office. The recent outbreak in California where 4 children were infected in their physician’s office reinforces the need for strict infection-control practices. Do not allow patients with rash and fever to remain in a common waiting area. Move them to an examination room, preferably an airborne infection isolation room. Keep the door to the examination room closed, and be sure that all health care personnel who come in contact with such patients are immune. Do not use triage rooms for 2 hours after the patient suspected of having measles leaves. Do not send these patients to other health care facilities, such as laboratories, unless infection control measures can be adhered to at those locations. Guidelines on infection control practices in health care settings are available.^9,10

Quick response

Quick control of these outbreaks shows the value of the public health infrastructure. Disease surveillance and outbreak response is vital to the public health system, and its value is frequently under-appreciated by physicians and the public.

Measles is still a threat. Endemic transmission of measles no longer occurs in the United States (or any of the Americas), yet this highly infectious disease is still a threat from importation by visitors from other countries and from US residents who have traveled abroad. Two recent outbreaks (described at left) illustrate these risks.

What the CDC discovered

The 2 outbreaks of import-linked measles brought home—literally—the sobering facts about vulnerability among US residents. The CDC report ^1,2 of its investigation observed:

US travelers can be exposed almost anywhere, developed countries included. The California outbreak started with a visit to Switzerland.

Measles spreads rapidly in susceptible subgroups, unless effective control strategies are used. In California, on 2 consecutive days, 5 school children and 4 children in a doctor’s office were infected; all were unvaccinated.

People not considered at risk can contract measles. Although 2 doses of vaccine are 99% effective, vaccinated individuals, such as the college students, can contract measles. Likewise, people born before 1957 may not be immune, in contrast to the general definition of immunity (see Measles Basics. Case in point: the airline passenger, born in 1954.

Disease can be severe. The 40-year-old salesperson (no documented vaccination) was hospitalized with seizure, 105ºF fever, and pneumonia. One of the infants was hospitalized due to dehydration.

People in routine contact with travelers entering the United States can be exposed to measles—like the airline worker.

Take-home lessons for family physicians

Include measles in the differential diagnosis of patients who have fever and rash, especially if they have traveled to another country within the past 3 to 4 weeks. Any patient who meets the definition of measles (fever 101ºF or higher; rash; and at least 1 of the 3 Cs—cough, coryza, conjunctivitis) should be immediately reported to the local health department. The health department will provide instructions for collecting laboratory samples for confirmation; instructions on patient isolation; and assistance with notification and disease control measures for exposed individuals.

Immunize patients and staff. These recurring cases of imported measles underscore the importance of maintaining a high level of immunity. Outbreaks can happen even where immunity is 90% to 95%. When vaccination rates dip below 90%, sustained outbreaks can occur.⁶

Ensure that staff and patients are all immunized against vaccine-preventable diseases, and inform concerned parents about the safety and effectiveness of vaccines. Parents who refuse to have their children vaccinated place their children at risk and contribute to higher community risk. Communities that have higher rates of non-adherence to vaccine recommendations are more likely to have outbreaks.^7,8

Use strict infection control in the office. The recent outbreak in California where 4 children were infected in their physician’s office reinforces the need for strict infection-control practices. Do not allow patients with rash and fever to remain in a common waiting area. Move them to an examination room, preferably an airborne infection isolation room. Keep the door to the examination room closed, and be sure that all health care personnel who come in contact with such patients are immune. Do not use triage rooms for 2 hours after the patient suspected of having measles leaves. Do not send these patients to other health care facilities, such as laboratories, unless infection control measures can be adhered to at those locations. Guidelines on infection control practices in health care settings are available.^9,10

Quick response

Quick control of these outbreaks shows the value of the public health infrastructure. Disease surveillance and outbreak response is vital to the public health system, and its value is frequently under-appreciated by physicians and the public.

Measles is still a threat. Endemic transmission of measles no longer occurs in the United States (or any of the Americas), yet this highly infectious disease is still a threat from importation by visitors from other countries and from US residents who have traveled abroad. Two recent outbreaks (described at left) illustrate these risks.

What the CDC discovered

The 2 outbreaks of import-linked measles brought home—literally—the sobering facts about vulnerability among US residents. The CDC report ^1,2 of its investigation observed:

US travelers can be exposed almost anywhere, developed countries included. The California outbreak started with a visit to Switzerland.

Measles spreads rapidly in susceptible subgroups, unless effective control strategies are used. In California, on 2 consecutive days, 5 school children and 4 children in a doctor’s office were infected; all were unvaccinated.

People not considered at risk can contract measles. Although 2 doses of vaccine are 99% effective, vaccinated individuals, such as the college students, can contract measles. Likewise, people born before 1957 may not be immune, in contrast to the general definition of immunity (see Measles Basics. Case in point: the airline passenger, born in 1954.

Disease can be severe. The 40-year-old salesperson (no documented vaccination) was hospitalized with seizure, 105ºF fever, and pneumonia. One of the infants was hospitalized due to dehydration.

People in routine contact with travelers entering the United States can be exposed to measles—like the airline worker.

Take-home lessons for family physicians

Include measles in the differential diagnosis of patients who have fever and rash, especially if they have traveled to another country within the past 3 to 4 weeks. Any patient who meets the definition of measles (fever 101ºF or higher; rash; and at least 1 of the 3 Cs—cough, coryza, conjunctivitis) should be immediately reported to the local health department. The health department will provide instructions for collecting laboratory samples for confirmation; instructions on patient isolation; and assistance with notification and disease control measures for exposed individuals.

Immunize patients and staff. These recurring cases of imported measles underscore the importance of maintaining a high level of immunity. Outbreaks can happen even where immunity is 90% to 95%. When vaccination rates dip below 90%, sustained outbreaks can occur.⁶

Ensure that staff and patients are all immunized against vaccine-preventable diseases, and inform concerned parents about the safety and effectiveness of vaccines. Parents who refuse to have their children vaccinated place their children at risk and contribute to higher community risk. Communities that have higher rates of non-adherence to vaccine recommendations are more likely to have outbreaks.^7,8

Use strict infection control in the office. The recent outbreak in California where 4 children were infected in their physician’s office reinforces the need for strict infection-control practices. Do not allow patients with rash and fever to remain in a common waiting area. Move them to an examination room, preferably an airborne infection isolation room. Keep the door to the examination room closed, and be sure that all health care personnel who come in contact with such patients are immune. Do not use triage rooms for 2 hours after the patient suspected of having measles leaves. Do not send these patients to other health care facilities, such as laboratories, unless infection control measures can be adhered to at those locations. Guidelines on infection control practices in health care settings are available.^9,10

Quick response

Quick control of these outbreaks shows the value of the public health infrastructure. Disease surveillance and outbreak response is vital to the public health system, and its value is frequently under-appreciated by physicians and the public.

We give you facts of an actual malpractice case. Submit your verdict below and see how your colleagues voted.

Did the patient know the risks of risperidone?

THE PATIENT. A 53-year-old woman hospitalized for depression and suicidal thoughts was prescribed risperidone.

CASE FACTS. The patient developed excessive mouth and tongue movement—including pursed lips, protruding tongue, and biting the inside of her mouth—and uncontrollable urges to move her extremities. She was diagnosed with probable tardive dyskinesia (TD), and risperidone was tapered and discontinued.

THE PATIENT’S CLAIM. The psychiatrist failed to adequately monitor her and recognize early symptoms of TD and did not tell the patient to look for signs of TD.

THE DOCTOR’S DEFENSE. None

Submit your verdict and find out how the court ruled. Click on “Have more to say about this topic?” to comment.

We give you facts of an actual malpractice case. Submit your verdict below and see how your colleagues voted.

Did the patient know the risks of risperidone?

THE PATIENT. A 53-year-old woman hospitalized for depression and suicidal thoughts was prescribed risperidone.

CASE FACTS. The patient developed excessive mouth and tongue movement—including pursed lips, protruding tongue, and biting the inside of her mouth—and uncontrollable urges to move her extremities. She was diagnosed with probable tardive dyskinesia (TD), and risperidone was tapered and discontinued.

THE PATIENT’S CLAIM. The psychiatrist failed to adequately monitor her and recognize early symptoms of TD and did not tell the patient to look for signs of TD.

THE DOCTOR’S DEFENSE. None

Submit your verdict and find out how the court ruled. Click on “Have more to say about this topic?” to comment.

We give you facts of an actual malpractice case. Submit your verdict below and see how your colleagues voted.

Did the patient know the risks of risperidone?

THE PATIENT. A 53-year-old woman hospitalized for depression and suicidal thoughts was prescribed risperidone.

CASE FACTS. The patient developed excessive mouth and tongue movement—including pursed lips, protruding tongue, and biting the inside of her mouth—and uncontrollable urges to move her extremities. She was diagnosed with probable tardive dyskinesia (TD), and risperidone was tapered and discontinued.

THE PATIENT’S CLAIM. The psychiatrist failed to adequately monitor her and recognize early symptoms of TD and did not tell the patient to look for signs of TD.

THE DOCTOR’S DEFENSE. None

Submit your verdict and find out how the court ruled. Click on “Have more to say about this topic?” to comment.

Dear Dr. Mossman,

I prescribed topiramate for Mr. B, a patient with no history of kidney stones. Many months later he developed back pain. During the medical workup for a possible kidney stone, Mr. B and I revisited the risk of kidney stones with topiramate, which we had discussed at the beginning of therapy. Mr. B was adamantly opposed to stopping topiramate, even if he had a kidney stone. Testing revealed that Mr. B did not have a stone, but I wasn’t sure how to proceed. I worried that I might be found liable if Mr. B stayed on topiramate and did develop a kidney stone.—Submitted by Dr. A

When a patient develops a medical problem from a drug you prescribed, it is natural to feel responsible—after all, your treatment caused the adverse event. But did you commit malpractice? To answer this, let’s review the concept of “medical negligence.”

Malpractice law applies legal principles of negligence to professional conduct.¹ The elements of a negligence case (Table 1) can be summarized as “breach of duty causing damages.” Therefore, when you wonder whether possible harm to a patient might be considered malpractice, ask yourself, “Did I breach my professional duty?”

Physicians have a duty to practice within their specialty’s standard of care, and if they do this, they should not be held liable even if their treatments cause adverse effects. Each jurisdiction defines the standard of care differently, but the general expectation is “that physicians acting within the ambit of their professional work will exercise the skill, knowledge, and care normally possessed and exercised by other members of their profession…in the relevant medical community.”¹

It’s impossible to describe all the skills, knowledge, and care a psychiatrist normally employs when prescribing a drug, but elements of good practice include reasonable efforts to:

• make an appropriate diagnosis
  
• offer appropriate treatment
  
• monitor effects of treatment.
  

Further, treatment should occur only when a patient gives informed consent. Let’s examine each of these elements as they apply to Dr. A and Mr. B.

Table 1

Elements of a successful negligence case

Appropriate assessment

Despite the availability of guidelines for psychiatric evaluation,^2,3 it is tough to summarize everything psychiatrists do when assessing patients. But—focusing on Dr. A’s question—it is reasonable to ask: Did the psychiatric evaluation provide reasonably good evidence that Mr. B had a condition that topiramate might alleviate? Mr. B’s strong desire to keep taking the drug suggests that the answer is “yes.”

Dr. A also should consider potential interactions between topiramate and any other medications that Mr. B is taking. A prudent clinician must judge whether the potential benefit of topiramate for Mr. B outweighs the risk of adverse effects. If Mr. B actually had developed a kidney stone, Dr. A might seek a nephrologist’s advice about how to minimize the risk of recurrence.

Appropriate treatment

Topiramate is FDA-approved only for treating seizures and for prophylaxis against migraine headaches. However, FDA approval limits only how pharmaceutical companies can promote a medication.⁴ Physicians may prescribe drugs for unapproved “off-label” uses, and doing so is accepted medical practice. Peer-reviewed publications support using topiramate to treat agitation,⁵ alcohol dependence,⁶ binge-eating disorder,⁷ and other conditions that psychiatrists often manage. A tendency to promote weight loss has made topiramate an attractive add-on medication for patients whose weight problems are causing other health difficulties.⁸

Assuming that Mr. B is taking topiramate for an off-label purpose, an appropriate question to ask is, “Does professional literature support use of topiramate in Mr. B’s circumstances?” Also, given everything known about Mr. B up to this point, is topiramate a good treatment choice?

Appropriate monitoring

As every clinician knows, medications can cause problems. Monitoring topiramate therapy involves periodic lab testing and assessment of effectiveness. Dr. A should feel reasonably sure that Mr. B—assisted by a family member or close friend, if necessary—can and will cooperate with monitoring requirements. Dr. A also should verify that Mr. B can grasp and follow instructions designed to avert complications—such as ample hydration to reduce risk of nephrolithiasis—and will promptly address problems if they occur.

Informed consent

Informed consent is especially important when a patient receives a treatment that has a known risk. Although the Physician’s Desk Reference does not list previous kidney stones as a contraindication to topiramate therapy, it urges caution under these circumstances.⁴ Therefore, if Dr. A wishes to prescribe topiramate for a patient with a history of kidney stone, the patient should meaningfully collaborate in the treatment decision.

Informed consent for treatment requires that patients not feel coerced by the doctor or setting and have the mental capacity or competence to give consent. Under the conceptualization developed by Appelbaum and Grisso,⁹ competent patients can:

• express a consistent choice
  
• understand medical information provided to them
  
• appreciate how this information applies to them and their condition
  
• reason logically about treatment.
  

Table 2

Evaluating a patient’s capacity to consent to treatment

Dear Dr. Mossman,

I prescribed topiramate for Mr. B, a patient with no history of kidney stones. Many months later he developed back pain. During the medical workup for a possible kidney stone, Mr. B and I revisited the risk of kidney stones with topiramate, which we had discussed at the beginning of therapy. Mr. B was adamantly opposed to stopping topiramate, even if he had a kidney stone. Testing revealed that Mr. B did not have a stone, but I wasn’t sure how to proceed. I worried that I might be found liable if Mr. B stayed on topiramate and did develop a kidney stone.—Submitted by Dr. A

When a patient develops a medical problem from a drug you prescribed, it is natural to feel responsible—after all, your treatment caused the adverse event. But did you commit malpractice? To answer this, let’s review the concept of “medical negligence.”

Malpractice law applies legal principles of negligence to professional conduct.¹ The elements of a negligence case (Table 1) can be summarized as “breach of duty causing damages.” Therefore, when you wonder whether possible harm to a patient might be considered malpractice, ask yourself, “Did I breach my professional duty?”

Physicians have a duty to practice within their specialty’s standard of care, and if they do this, they should not be held liable even if their treatments cause adverse effects. Each jurisdiction defines the standard of care differently, but the general expectation is “that physicians acting within the ambit of their professional work will exercise the skill, knowledge, and care normally possessed and exercised by other members of their profession…in the relevant medical community.”¹

It’s impossible to describe all the skills, knowledge, and care a psychiatrist normally employs when prescribing a drug, but elements of good practice include reasonable efforts to:

• make an appropriate diagnosis
  
• offer appropriate treatment
  
• monitor effects of treatment.
  

Further, treatment should occur only when a patient gives informed consent. Let’s examine each of these elements as they apply to Dr. A and Mr. B.

Table 1

Elements of a successful negligence case

Appropriate assessment

Despite the availability of guidelines for psychiatric evaluation,^2,3 it is tough to summarize everything psychiatrists do when assessing patients. But—focusing on Dr. A’s question—it is reasonable to ask: Did the psychiatric evaluation provide reasonably good evidence that Mr. B had a condition that topiramate might alleviate? Mr. B’s strong desire to keep taking the drug suggests that the answer is “yes.”

Dr. A also should consider potential interactions between topiramate and any other medications that Mr. B is taking. A prudent clinician must judge whether the potential benefit of topiramate for Mr. B outweighs the risk of adverse effects. If Mr. B actually had developed a kidney stone, Dr. A might seek a nephrologist’s advice about how to minimize the risk of recurrence.

Appropriate treatment

Topiramate is FDA-approved only for treating seizures and for prophylaxis against migraine headaches. However, FDA approval limits only how pharmaceutical companies can promote a medication.⁴ Physicians may prescribe drugs for unapproved “off-label” uses, and doing so is accepted medical practice. Peer-reviewed publications support using topiramate to treat agitation,⁵ alcohol dependence,⁶ binge-eating disorder,⁷ and other conditions that psychiatrists often manage. A tendency to promote weight loss has made topiramate an attractive add-on medication for patients whose weight problems are causing other health difficulties.⁸

Assuming that Mr. B is taking topiramate for an off-label purpose, an appropriate question to ask is, “Does professional literature support use of topiramate in Mr. B’s circumstances?” Also, given everything known about Mr. B up to this point, is topiramate a good treatment choice?

Appropriate monitoring

As every clinician knows, medications can cause problems. Monitoring topiramate therapy involves periodic lab testing and assessment of effectiveness. Dr. A should feel reasonably sure that Mr. B—assisted by a family member or close friend, if necessary—can and will cooperate with monitoring requirements. Dr. A also should verify that Mr. B can grasp and follow instructions designed to avert complications—such as ample hydration to reduce risk of nephrolithiasis—and will promptly address problems if they occur.

Informed consent

Informed consent is especially important when a patient receives a treatment that has a known risk. Although the Physician’s Desk Reference does not list previous kidney stones as a contraindication to topiramate therapy, it urges caution under these circumstances.⁴ Therefore, if Dr. A wishes to prescribe topiramate for a patient with a history of kidney stone, the patient should meaningfully collaborate in the treatment decision.

Informed consent for treatment requires that patients not feel coerced by the doctor or setting and have the mental capacity or competence to give consent. Under the conceptualization developed by Appelbaum and Grisso,⁹ competent patients can:

• express a consistent choice
  
• understand medical information provided to them
  
• appreciate how this information applies to them and their condition
  
• reason logically about treatment.
  

Table 2

Evaluating a patient’s capacity to consent to treatment

Dear Dr. Mossman,

I prescribed topiramate for Mr. B, a patient with no history of kidney stones. Many months later he developed back pain. During the medical workup for a possible kidney stone, Mr. B and I revisited the risk of kidney stones with topiramate, which we had discussed at the beginning of therapy. Mr. B was adamantly opposed to stopping topiramate, even if he had a kidney stone. Testing revealed that Mr. B did not have a stone, but I wasn’t sure how to proceed. I worried that I might be found liable if Mr. B stayed on topiramate and did develop a kidney stone.—Submitted by Dr. A

When a patient develops a medical problem from a drug you prescribed, it is natural to feel responsible—after all, your treatment caused the adverse event. But did you commit malpractice? To answer this, let’s review the concept of “medical negligence.”

Malpractice law applies legal principles of negligence to professional conduct.¹ The elements of a negligence case (Table 1) can be summarized as “breach of duty causing damages.” Therefore, when you wonder whether possible harm to a patient might be considered malpractice, ask yourself, “Did I breach my professional duty?”

Physicians have a duty to practice within their specialty’s standard of care, and if they do this, they should not be held liable even if their treatments cause adverse effects. Each jurisdiction defines the standard of care differently, but the general expectation is “that physicians acting within the ambit of their professional work will exercise the skill, knowledge, and care normally possessed and exercised by other members of their profession…in the relevant medical community.”¹

It’s impossible to describe all the skills, knowledge, and care a psychiatrist normally employs when prescribing a drug, but elements of good practice include reasonable efforts to:

• make an appropriate diagnosis
  
• offer appropriate treatment
  
• monitor effects of treatment.
  

Further, treatment should occur only when a patient gives informed consent. Let’s examine each of these elements as they apply to Dr. A and Mr. B.

Table 1

Elements of a successful negligence case

Appropriate assessment

Despite the availability of guidelines for psychiatric evaluation,^2,3 it is tough to summarize everything psychiatrists do when assessing patients. But—focusing on Dr. A’s question—it is reasonable to ask: Did the psychiatric evaluation provide reasonably good evidence that Mr. B had a condition that topiramate might alleviate? Mr. B’s strong desire to keep taking the drug suggests that the answer is “yes.”

Dr. A also should consider potential interactions between topiramate and any other medications that Mr. B is taking. A prudent clinician must judge whether the potential benefit of topiramate for Mr. B outweighs the risk of adverse effects. If Mr. B actually had developed a kidney stone, Dr. A might seek a nephrologist’s advice about how to minimize the risk of recurrence.

Appropriate treatment

Topiramate is FDA-approved only for treating seizures and for prophylaxis against migraine headaches. However, FDA approval limits only how pharmaceutical companies can promote a medication.⁴ Physicians may prescribe drugs for unapproved “off-label” uses, and doing so is accepted medical practice. Peer-reviewed publications support using topiramate to treat agitation,⁵ alcohol dependence,⁶ binge-eating disorder,⁷ and other conditions that psychiatrists often manage. A tendency to promote weight loss has made topiramate an attractive add-on medication for patients whose weight problems are causing other health difficulties.⁸

Assuming that Mr. B is taking topiramate for an off-label purpose, an appropriate question to ask is, “Does professional literature support use of topiramate in Mr. B’s circumstances?” Also, given everything known about Mr. B up to this point, is topiramate a good treatment choice?

Appropriate monitoring

As every clinician knows, medications can cause problems. Monitoring topiramate therapy involves periodic lab testing and assessment of effectiveness. Dr. A should feel reasonably sure that Mr. B—assisted by a family member or close friend, if necessary—can and will cooperate with monitoring requirements. Dr. A also should verify that Mr. B can grasp and follow instructions designed to avert complications—such as ample hydration to reduce risk of nephrolithiasis—and will promptly address problems if they occur.

Informed consent

Informed consent is especially important when a patient receives a treatment that has a known risk. Although the Physician’s Desk Reference does not list previous kidney stones as a contraindication to topiramate therapy, it urges caution under these circumstances.⁴ Therefore, if Dr. A wishes to prescribe topiramate for a patient with a history of kidney stone, the patient should meaningfully collaborate in the treatment decision.

Informed consent for treatment requires that patients not feel coerced by the doctor or setting and have the mental capacity or competence to give consent. Under the conceptualization developed by Appelbaum and Grisso,⁹ competent patients can:

• express a consistent choice
  
• understand medical information provided to them
  
• appreciate how this information applies to them and their condition
  
• reason logically about treatment.
  

Table 2

Evaluating a patient’s capacity to consent to treatment

The US Food and Drug Administration (FDA) has identified the structure and source of the contaminant found in lots of heparin.

The contaminant, which has been linked to severe allergic reactions and deaths, was found in crude lots of heparin at a Chinese processing plant. The substance has been identified as over-sulfated chondroitin sulfate.

Researchers initially had difficulty identifying the contaminant because it is so similar to heparin. Over-sulfated chondroitin sulfate has approximately the same molecular weight as heparin, and both materials belong to the class of molecules known as glucosaminoglycans (GAGs).

It is still unknown whether the over-sulfated chondroitin sulfate was a byproduct of the heparin production process or if it was intentionally added to the active pharmaceutical ingredient.

After learning about the source of the over-sulfated chondroitin sulfate, the FDA issued a border alert that requires all finished heparin, as well as heparin source material, to be tested before it is allowed into the US. Five heparin manufacturers, companies that supply most of the heparin used in this country, have agreed to conduct the tests.

Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said the agency would test heparin products made by companies that cannot conduct the testing themselves. Any product that is not tested or fails the tests will be destroyed.

Scientific Protein Laboratories is the company that supplied crude heparin from the Changzhou plant in China to the biopharmaceutical company Baxter. Scientific Protein Laboratories has said it is cooperating with the FDA, and the Changzhou plant is not currently producing heparin.

In addition to the new testing instituted at the US borders, the FDA said heparin testing is now being conducted worldwide. Germany and Japan are among the countries that have started testing.

Germany recalled heparin last week after a cluster of about 100 serious allergic reactions, including hypotension and anaphylaxis. Japan has also recalled heparin but has not reported any adverse events linked to heparin injections.

Both Scientific Protein Laboratories and Baxter have conducted massive voluntary recalls of heparin products. Since Baxter recalled all of its heparin vials, there have been no additional deaths.

Last week, the FDA received 785 reports of adverse events associated with heparin. Those reports included 46 deaths, but Dr Woodcock said only 19 were related to the allergic profile associated with the Baxter heparin.

Baxter has said it cannot confirm that heparin has caused any fatalities as a result of an allergic reaction. The company said there are 4 cases in which patients received Baxter heparin and suffered an allergic-type reaction to the drug.

Baxter also said there is not yet enough medical data available to draw a firm conclusion that the reaction caused death. In each of these cases, the patient had multiple underlying complex medical conditions. Three of the 4 patients had undergone, or were in the process of undergoing, invasive cardiac surgery.

The heparin saga began January 17 of this year, when Baxter recalled the first batch of heparin after receiving reports of the allergic reactions. Recalls of the drug have continued since that time.

The FDA released the news of the contaminant’s source March 14 and the discovery of its structure March 19.

The US Food and Drug Administration (FDA) has identified the structure and source of the contaminant found in lots of heparin.

The contaminant, which has been linked to severe allergic reactions and deaths, was found in crude lots of heparin at a Chinese processing plant. The substance has been identified as over-sulfated chondroitin sulfate.

Researchers initially had difficulty identifying the contaminant because it is so similar to heparin. Over-sulfated chondroitin sulfate has approximately the same molecular weight as heparin, and both materials belong to the class of molecules known as glucosaminoglycans (GAGs).

It is still unknown whether the over-sulfated chondroitin sulfate was a byproduct of the heparin production process or if it was intentionally added to the active pharmaceutical ingredient.

After learning about the source of the over-sulfated chondroitin sulfate, the FDA issued a border alert that requires all finished heparin, as well as heparin source material, to be tested before it is allowed into the US. Five heparin manufacturers, companies that supply most of the heparin used in this country, have agreed to conduct the tests.

Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said the agency would test heparin products made by companies that cannot conduct the testing themselves. Any product that is not tested or fails the tests will be destroyed.

Scientific Protein Laboratories is the company that supplied crude heparin from the Changzhou plant in China to the biopharmaceutical company Baxter. Scientific Protein Laboratories has said it is cooperating with the FDA, and the Changzhou plant is not currently producing heparin.

In addition to the new testing instituted at the US borders, the FDA said heparin testing is now being conducted worldwide. Germany and Japan are among the countries that have started testing.

Germany recalled heparin last week after a cluster of about 100 serious allergic reactions, including hypotension and anaphylaxis. Japan has also recalled heparin but has not reported any adverse events linked to heparin injections.

Both Scientific Protein Laboratories and Baxter have conducted massive voluntary recalls of heparin products. Since Baxter recalled all of its heparin vials, there have been no additional deaths.

Last week, the FDA received 785 reports of adverse events associated with heparin. Those reports included 46 deaths, but Dr Woodcock said only 19 were related to the allergic profile associated with the Baxter heparin.

Baxter has said it cannot confirm that heparin has caused any fatalities as a result of an allergic reaction. The company said there are 4 cases in which patients received Baxter heparin and suffered an allergic-type reaction to the drug.

Baxter also said there is not yet enough medical data available to draw a firm conclusion that the reaction caused death. In each of these cases, the patient had multiple underlying complex medical conditions. Three of the 4 patients had undergone, or were in the process of undergoing, invasive cardiac surgery.

The heparin saga began January 17 of this year, when Baxter recalled the first batch of heparin after receiving reports of the allergic reactions. Recalls of the drug have continued since that time.

The FDA released the news of the contaminant’s source March 14 and the discovery of its structure March 19.

The US Food and Drug Administration (FDA) has identified the structure and source of the contaminant found in lots of heparin.

The contaminant, which has been linked to severe allergic reactions and deaths, was found in crude lots of heparin at a Chinese processing plant. The substance has been identified as over-sulfated chondroitin sulfate.

Researchers initially had difficulty identifying the contaminant because it is so similar to heparin. Over-sulfated chondroitin sulfate has approximately the same molecular weight as heparin, and both materials belong to the class of molecules known as glucosaminoglycans (GAGs).

It is still unknown whether the over-sulfated chondroitin sulfate was a byproduct of the heparin production process or if it was intentionally added to the active pharmaceutical ingredient.

After learning about the source of the over-sulfated chondroitin sulfate, the FDA issued a border alert that requires all finished heparin, as well as heparin source material, to be tested before it is allowed into the US. Five heparin manufacturers, companies that supply most of the heparin used in this country, have agreed to conduct the tests.

Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said the agency would test heparin products made by companies that cannot conduct the testing themselves. Any product that is not tested or fails the tests will be destroyed.

Scientific Protein Laboratories is the company that supplied crude heparin from the Changzhou plant in China to the biopharmaceutical company Baxter. Scientific Protein Laboratories has said it is cooperating with the FDA, and the Changzhou plant is not currently producing heparin.

In addition to the new testing instituted at the US borders, the FDA said heparin testing is now being conducted worldwide. Germany and Japan are among the countries that have started testing.

Germany recalled heparin last week after a cluster of about 100 serious allergic reactions, including hypotension and anaphylaxis. Japan has also recalled heparin but has not reported any adverse events linked to heparin injections.

Both Scientific Protein Laboratories and Baxter have conducted massive voluntary recalls of heparin products. Since Baxter recalled all of its heparin vials, there have been no additional deaths.

Last week, the FDA received 785 reports of adverse events associated with heparin. Those reports included 46 deaths, but Dr Woodcock said only 19 were related to the allergic profile associated with the Baxter heparin.

Baxter has said it cannot confirm that heparin has caused any fatalities as a result of an allergic reaction. The company said there are 4 cases in which patients received Baxter heparin and suffered an allergic-type reaction to the drug.

Baxter also said there is not yet enough medical data available to draw a firm conclusion that the reaction caused death. In each of these cases, the patient had multiple underlying complex medical conditions. Three of the 4 patients had undergone, or were in the process of undergoing, invasive cardiac surgery.

The heparin saga began January 17 of this year, when Baxter recalled the first batch of heparin after receiving reports of the allergic reactions. Recalls of the drug have continued since that time.

The FDA released the news of the contaminant’s source March 14 and the discovery of its structure March 19.

Supplement Editor:
Marc S. Penn, MD, PhD

Contents*^†

Introduction: Heart-brain medicine: Update 2007
Marc S. Penn, MD, PhD, and Earl E. Bakken, MD, HonC, (3) SciDHon

Depression in coronary artery disease: Does treatment help?
Peter A. Shapiro, MD

Case study in heart-brain interplay: A 53-year-old woman recovering from mitral valve repair
Thomas D. Callahan, IV, MD; Ubaid Khokhar, MD; Leo Pozuelo, MD; and James B. Young, MD

Emotional predictors and behavioral triggers of acute coronary syndrome
Karina W. Davidson, PhD

Impacts of depression and emotional distress on cardiac disease
Wei Jiang, MD

Inflammation as a link between brain injury and heart damage: The model of subarachnoid hemorrhage
Hazem Antar Mashaly, MD, and J. Javier Provencio, MD

Biofeedback: An overview in the context of heart-brain medicine
Michael G. McKee, PhD

Biofeedback therapy in cardiovascular disease: Rationale and research overview
Christine S. Moravec, PhD

Helping children and adults with hypnosis and biofeedback
Karen Olness, MD

Clinical hypnosis for reduction of atrial fibrillation after coronary artery bypass graft surgery
Roberto Novoa, MD, and Tracy Hammonds, BA

Depression and coronary heart disease: Association and implications for treatment
James A. Blumenthal, PhD

Cardiovascular autonomic dysfunction in patients with movement disorders
Benjamin L. Walter, MD

Deep brain stimulation: How does it work?
Jerrold L. Vitek, MD, PhD

Sudden unexpected death in epilepsy: Impact, mechanisms, and prevention
Lara Jehi, MD, and Imad M. Najm, MD

Evaluating brain function in patients with disorders of consciousness
Tristan Bekinschtein, PhD, and Facundo Manes, MD

Preconditioning paradigms and pathways in the brain
Karl B. Shpargel; Walid Jalabi, PhD; Yongming Jin; Alisher Dadabayev, MD; Marc S. Penn, MD, PhD,
and Bruce D. Trapp, PhD

Post-stroke exercise rehabilitation:What we know about retraining the motor system and how it may apply to retraining the heart
Andreas Luft, MD; Richard Macko, MD; Larry Forrester, PhD; Andrew Goldberg, MD; and Daniel F. Hanley, MD

Hippocampal volume change in the Alzheimer Disease Cholesterol-Lowering Treatment trial
D. Larry Sparks, PhD; Susan K. Lemieux, PhD; Marc W. Haut, PhD; Leslie C. Baxter, PhD; Sterling C. Johnson, PhD; Lisa M. Sparks, BS; Hemalatha Sampath, BSEE; Jean E. Lopez, RN; Marwan H. Sabbagh, MD; and Donald J. Connor, PhD

Heart-brain interactions in cardiac arrhythmias: Role of the autonomic nervous system
Douglas P. Zipes, MD

Insular Alzheimer disease pathology and the psychometric correlates of mortality
Donald R. Royall, MD

Poster abstracts


* These proceedings represent the large majority of presentations at the 2nd Heart-Brain Summit, but five Summit presentations were not able to be captured for publication here.

† Articles in these proceedings were either submitted as manuscripts by the Summit faculty or developed by the Cleveland Clinic Journal of Medicine staff from transcripts of audiotaped Summit presentations and then revised and approved by the Summit faculty.
 

Supplement Editor:
Marc S. Penn, MD, PhD

Contents*^†

Introduction: Heart-brain medicine: Update 2007
Marc S. Penn, MD, PhD, and Earl E. Bakken, MD, HonC, (3) SciDHon

Depression in coronary artery disease: Does treatment help?
Peter A. Shapiro, MD

Case study in heart-brain interplay: A 53-year-old woman recovering from mitral valve repair
Thomas D. Callahan, IV, MD; Ubaid Khokhar, MD; Leo Pozuelo, MD; and James B. Young, MD

Emotional predictors and behavioral triggers of acute coronary syndrome
Karina W. Davidson, PhD

Impacts of depression and emotional distress on cardiac disease
Wei Jiang, MD

Inflammation as a link between brain injury and heart damage: The model of subarachnoid hemorrhage
Hazem Antar Mashaly, MD, and J. Javier Provencio, MD

Biofeedback: An overview in the context of heart-brain medicine
Michael G. McKee, PhD

Biofeedback therapy in cardiovascular disease: Rationale and research overview
Christine S. Moravec, PhD

Helping children and adults with hypnosis and biofeedback
Karen Olness, MD

Clinical hypnosis for reduction of atrial fibrillation after coronary artery bypass graft surgery
Roberto Novoa, MD, and Tracy Hammonds, BA

Depression and coronary heart disease: Association and implications for treatment
James A. Blumenthal, PhD

Cardiovascular autonomic dysfunction in patients with movement disorders
Benjamin L. Walter, MD

Deep brain stimulation: How does it work?
Jerrold L. Vitek, MD, PhD

Sudden unexpected death in epilepsy: Impact, mechanisms, and prevention
Lara Jehi, MD, and Imad M. Najm, MD

Evaluating brain function in patients with disorders of consciousness
Tristan Bekinschtein, PhD, and Facundo Manes, MD

Preconditioning paradigms and pathways in the brain
Karl B. Shpargel; Walid Jalabi, PhD; Yongming Jin; Alisher Dadabayev, MD; Marc S. Penn, MD, PhD,
and Bruce D. Trapp, PhD

Post-stroke exercise rehabilitation:What we know about retraining the motor system and how it may apply to retraining the heart
Andreas Luft, MD; Richard Macko, MD; Larry Forrester, PhD; Andrew Goldberg, MD; and Daniel F. Hanley, MD

Hippocampal volume change in the Alzheimer Disease Cholesterol-Lowering Treatment trial
D. Larry Sparks, PhD; Susan K. Lemieux, PhD; Marc W. Haut, PhD; Leslie C. Baxter, PhD; Sterling C. Johnson, PhD; Lisa M. Sparks, BS; Hemalatha Sampath, BSEE; Jean E. Lopez, RN; Marwan H. Sabbagh, MD; and Donald J. Connor, PhD

Heart-brain interactions in cardiac arrhythmias: Role of the autonomic nervous system
Douglas P. Zipes, MD

Insular Alzheimer disease pathology and the psychometric correlates of mortality
Donald R. Royall, MD

Poster abstracts


* These proceedings represent the large majority of presentations at the 2nd Heart-Brain Summit, but five Summit presentations were not able to be captured for publication here.

† Articles in these proceedings were either submitted as manuscripts by the Summit faculty or developed by the Cleveland Clinic Journal of Medicine staff from transcripts of audiotaped Summit presentations and then revised and approved by the Summit faculty.
 

Supplement Editor:
Marc S. Penn, MD, PhD

Contents*^†

Introduction: Heart-brain medicine: Update 2007
Marc S. Penn, MD, PhD, and Earl E. Bakken, MD, HonC, (3) SciDHon

Depression in coronary artery disease: Does treatment help?
Peter A. Shapiro, MD

Case study in heart-brain interplay: A 53-year-old woman recovering from mitral valve repair
Thomas D. Callahan, IV, MD; Ubaid Khokhar, MD; Leo Pozuelo, MD; and James B. Young, MD

Emotional predictors and behavioral triggers of acute coronary syndrome
Karina W. Davidson, PhD

Impacts of depression and emotional distress on cardiac disease
Wei Jiang, MD

Inflammation as a link between brain injury and heart damage: The model of subarachnoid hemorrhage
Hazem Antar Mashaly, MD, and J. Javier Provencio, MD

Biofeedback: An overview in the context of heart-brain medicine
Michael G. McKee, PhD

Biofeedback therapy in cardiovascular disease: Rationale and research overview
Christine S. Moravec, PhD

Helping children and adults with hypnosis and biofeedback
Karen Olness, MD

Clinical hypnosis for reduction of atrial fibrillation after coronary artery bypass graft surgery
Roberto Novoa, MD, and Tracy Hammonds, BA

Depression and coronary heart disease: Association and implications for treatment
James A. Blumenthal, PhD

Cardiovascular autonomic dysfunction in patients with movement disorders
Benjamin L. Walter, MD

Deep brain stimulation: How does it work?
Jerrold L. Vitek, MD, PhD

Sudden unexpected death in epilepsy: Impact, mechanisms, and prevention
Lara Jehi, MD, and Imad M. Najm, MD

Evaluating brain function in patients with disorders of consciousness
Tristan Bekinschtein, PhD, and Facundo Manes, MD

Preconditioning paradigms and pathways in the brain
Karl B. Shpargel; Walid Jalabi, PhD; Yongming Jin; Alisher Dadabayev, MD; Marc S. Penn, MD, PhD,
and Bruce D. Trapp, PhD

Post-stroke exercise rehabilitation:What we know about retraining the motor system and how it may apply to retraining the heart
Andreas Luft, MD; Richard Macko, MD; Larry Forrester, PhD; Andrew Goldberg, MD; and Daniel F. Hanley, MD

Hippocampal volume change in the Alzheimer Disease Cholesterol-Lowering Treatment trial
D. Larry Sparks, PhD; Susan K. Lemieux, PhD; Marc W. Haut, PhD; Leslie C. Baxter, PhD; Sterling C. Johnson, PhD; Lisa M. Sparks, BS; Hemalatha Sampath, BSEE; Jean E. Lopez, RN; Marwan H. Sabbagh, MD; and Donald J. Connor, PhD

Heart-brain interactions in cardiac arrhythmias: Role of the autonomic nervous system
Douglas P. Zipes, MD

Insular Alzheimer disease pathology and the psychometric correlates of mortality
Donald R. Royall, MD

Poster abstracts


* These proceedings represent the large majority of presentations at the 2nd Heart-Brain Summit, but five Summit presentations were not able to be captured for publication here.

† Articles in these proceedings were either submitted as manuscripts by the Summit faculty or developed by the Cleveland Clinic Journal of Medicine staff from transcripts of audiotaped Summit presentations and then revised and approved by the Summit faculty.