These important questions are answered in a guideline developed by a committee of the American College of Chest Physicians, which considered the following prophylaxis recommendations: early ambulation, aspirin, graduated compression stockings, intermittent pneumatic compression, low-dose unfractionated heparin, low-molecular-weight heparin, or oral antithrombotic agents.

The committee categorized recommendations by type of surgical procedure and risk status. In this summary, the recommendations are reorganized by strength of recommendation.

Three outcomes were regarded:

1. Efficacy of various prophylactic strategies
2. Rates and relative risk of venous thromboembolism outcomes—ie, fatal pulmonary embolism, symptomatic deep vein thrombosis, pulmonary embolism, or asymptomatic proximal deep vein thrombosis
3. Cost-effectiveness of prophylaxis.

The committee used a rating scheme that accounted for both the risk/benefit ratio (clear or unclear) and the strength of the supporting recommendation (A, B, C). The grades of evidence were altered to correspond to the grades of recommendation of the Oxford Centre for Evidence-Based Medicine. (For an explanaton of these grades.)

Relevant recommendations

This guideline is clinically relevant because of the high mortality associated with pulmonary embolus complicating VTE.

It offers a practical, tabulated guide, listed by surgical procedure performed. It is pertinent to hospitalized patients under the care of family physicians. The rationale for each recommendation is clear and well supported by the referenced literature. The objectives of the guideline were met and the outcome measures were appropriate.

The guideline is weakened by the lack of cost-effectiveness considerations.

Guideline development and evidence review

Literature searches were performed for each patient group. Criteria for inclusion included relevant patient group, sample size of at least 10 patients per group, verified deep vein thrombosis, and patients with adequate outcome assessments.

In considering baseline risk of thrombosis, only either prospective cohort studies or control groups of randomized trials were considered. For prophylaxis efficacy recommendations, only randomized trials were considered. The consensus group analyzed data from 630 sources before making these recommendations.

Sources for this guideline

Sixth ACCP Consensus Conference on Antithrombotic Therapy

The Consensus Conference guidelines can be found at:

Geerts WH, et al. Prevention of thromboembolism. Chest 2001; 119:132S–175S. Available at: www.chestjournal.org/content/vol119/1_suppl/index. shtml. Accessed on December 16, 2003.

Tables illustrating these guideline, organized by type of surgical procedure can be accessed at: chestnet.safeserver.com/guidelines/antithrombotic/p8.php

In the same issue of this journal, there were reports on the mechanism of action for oral anticoagulants, managing oral anticoagulant therapy, platelet active drugs, mechanisms of action of heparin and low molecular weight heparin, hemorrhagic complications of anticoagulation, use of antithrombotic medications during pregnancy, antithrombotic therapy for heart disease and peripheral vascular disease, use of these for stroke, and their role in treating children.

OTHER GUIDELINES ON PREVENTION OF VTE

• Deep venous thrombosis. Finnish Medical Society Duodecim. Helsinki, Finland: Duodecim Publications Ltd; 2002. Available at: www.ngc.gov/guidelines/FTNGC-2610.html. Accessed on December 16, 2003.
• Practice paramenters for the prevention of venous thromboembolism. The Standards Task Force of the Society of Colon and Rectal Surgeons. Dis Colon Rectum 2000; 43:1037–47. [54 references.] Available at: www.fascrs.org/ascrspp-pvt.html. Accessed on December 16, 2003.

Correspondence
Keith B. Holten, MD, Clinton Memorial Hospital/University of Cincinnati Family Practice Residency, 825 W. Locust St., Wilmington, OH, 45177. E-mail: [email protected].

These important questions are answered in a guideline developed by a committee of the American College of Chest Physicians, which considered the following prophylaxis recommendations: early ambulation, aspirin, graduated compression stockings, intermittent pneumatic compression, low-dose unfractionated heparin, low-molecular-weight heparin, or oral antithrombotic agents.

The committee categorized recommendations by type of surgical procedure and risk status. In this summary, the recommendations are reorganized by strength of recommendation.

Three outcomes were regarded:

1. Efficacy of various prophylactic strategies
2. Rates and relative risk of venous thromboembolism outcomes—ie, fatal pulmonary embolism, symptomatic deep vein thrombosis, pulmonary embolism, or asymptomatic proximal deep vein thrombosis
3. Cost-effectiveness of prophylaxis.

The committee used a rating scheme that accounted for both the risk/benefit ratio (clear or unclear) and the strength of the supporting recommendation (A, B, C). The grades of evidence were altered to correspond to the grades of recommendation of the Oxford Centre for Evidence-Based Medicine. (For an explanaton of these grades.)

Relevant recommendations

This guideline is clinically relevant because of the high mortality associated with pulmonary embolus complicating VTE.

It offers a practical, tabulated guide, listed by surgical procedure performed. It is pertinent to hospitalized patients under the care of family physicians. The rationale for each recommendation is clear and well supported by the referenced literature. The objectives of the guideline were met and the outcome measures were appropriate.

The guideline is weakened by the lack of cost-effectiveness considerations.

Guideline development and evidence review

Literature searches were performed for each patient group. Criteria for inclusion included relevant patient group, sample size of at least 10 patients per group, verified deep vein thrombosis, and patients with adequate outcome assessments.

In considering baseline risk of thrombosis, only either prospective cohort studies or control groups of randomized trials were considered. For prophylaxis efficacy recommendations, only randomized trials were considered. The consensus group analyzed data from 630 sources before making these recommendations.

Sources for this guideline

Sixth ACCP Consensus Conference on Antithrombotic Therapy

The Consensus Conference guidelines can be found at:

Geerts WH, et al. Prevention of thromboembolism. Chest 2001; 119:132S–175S. Available at: www.chestjournal.org/content/vol119/1_suppl/index. shtml. Accessed on December 16, 2003.

Tables illustrating these guideline, organized by type of surgical procedure can be accessed at: chestnet.safeserver.com/guidelines/antithrombotic/p8.php

In the same issue of this journal, there were reports on the mechanism of action for oral anticoagulants, managing oral anticoagulant therapy, platelet active drugs, mechanisms of action of heparin and low molecular weight heparin, hemorrhagic complications of anticoagulation, use of antithrombotic medications during pregnancy, antithrombotic therapy for heart disease and peripheral vascular disease, use of these for stroke, and their role in treating children.

OTHER GUIDELINES ON PREVENTION OF VTE

• Deep venous thrombosis. Finnish Medical Society Duodecim. Helsinki, Finland: Duodecim Publications Ltd; 2002. Available at: www.ngc.gov/guidelines/FTNGC-2610.html. Accessed on December 16, 2003.
• Practice paramenters for the prevention of venous thromboembolism. The Standards Task Force of the Society of Colon and Rectal Surgeons. Dis Colon Rectum 2000; 43:1037–47. [54 references.] Available at: www.fascrs.org/ascrspp-pvt.html. Accessed on December 16, 2003.

Correspondence
Keith B. Holten, MD, Clinton Memorial Hospital/University of Cincinnati Family Practice Residency, 825 W. Locust St., Wilmington, OH, 45177. E-mail: [email protected].

These important questions are answered in a guideline developed by a committee of the American College of Chest Physicians, which considered the following prophylaxis recommendations: early ambulation, aspirin, graduated compression stockings, intermittent pneumatic compression, low-dose unfractionated heparin, low-molecular-weight heparin, or oral antithrombotic agents.

The committee categorized recommendations by type of surgical procedure and risk status. In this summary, the recommendations are reorganized by strength of recommendation.

Three outcomes were regarded:

1. Efficacy of various prophylactic strategies
2. Rates and relative risk of venous thromboembolism outcomes—ie, fatal pulmonary embolism, symptomatic deep vein thrombosis, pulmonary embolism, or asymptomatic proximal deep vein thrombosis
3. Cost-effectiveness of prophylaxis.

The committee used a rating scheme that accounted for both the risk/benefit ratio (clear or unclear) and the strength of the supporting recommendation (A, B, C). The grades of evidence were altered to correspond to the grades of recommendation of the Oxford Centre for Evidence-Based Medicine. (For an explanaton of these grades.)

Relevant recommendations

This guideline is clinically relevant because of the high mortality associated with pulmonary embolus complicating VTE.

It offers a practical, tabulated guide, listed by surgical procedure performed. It is pertinent to hospitalized patients under the care of family physicians. The rationale for each recommendation is clear and well supported by the referenced literature. The objectives of the guideline were met and the outcome measures were appropriate.

The guideline is weakened by the lack of cost-effectiveness considerations.

Guideline development and evidence review

Literature searches were performed for each patient group. Criteria for inclusion included relevant patient group, sample size of at least 10 patients per group, verified deep vein thrombosis, and patients with adequate outcome assessments.

In considering baseline risk of thrombosis, only either prospective cohort studies or control groups of randomized trials were considered. For prophylaxis efficacy recommendations, only randomized trials were considered. The consensus group analyzed data from 630 sources before making these recommendations.

Sources for this guideline

Sixth ACCP Consensus Conference on Antithrombotic Therapy

The Consensus Conference guidelines can be found at:

Geerts WH, et al. Prevention of thromboembolism. Chest 2001; 119:132S–175S. Available at: www.chestjournal.org/content/vol119/1_suppl/index. shtml. Accessed on December 16, 2003.

Tables illustrating these guideline, organized by type of surgical procedure can be accessed at: chestnet.safeserver.com/guidelines/antithrombotic/p8.php

In the same issue of this journal, there were reports on the mechanism of action for oral anticoagulants, managing oral anticoagulant therapy, platelet active drugs, mechanisms of action of heparin and low molecular weight heparin, hemorrhagic complications of anticoagulation, use of antithrombotic medications during pregnancy, antithrombotic therapy for heart disease and peripheral vascular disease, use of these for stroke, and their role in treating children.

OTHER GUIDELINES ON PREVENTION OF VTE

• Deep venous thrombosis. Finnish Medical Society Duodecim. Helsinki, Finland: Duodecim Publications Ltd; 2002. Available at: www.ngc.gov/guidelines/FTNGC-2610.html. Accessed on December 16, 2003.
• Practice paramenters for the prevention of venous thromboembolism. The Standards Task Force of the Society of Colon and Rectal Surgeons. Dis Colon Rectum 2000; 43:1037–47. [54 references.] Available at: www.fascrs.org/ascrspp-pvt.html. Accessed on December 16, 2003.

Correspondence
Keith B. Holten, MD, Clinton Memorial Hospital/University of Cincinnati Family Practice Residency, 825 W. Locust St., Wilmington, OH, 45177. E-mail: [email protected].

As America’s population ages, the need to find new treatments for Alzheimer’s disease (AD) is increasingly urgent. Agents that have reached the medical mainstream in recent years target the disease in its mild to moderate stages. Memantine recently gained FDA approval for treating moderate to severe AD.

HOW IT WORKS

Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. NMDA receptors mediate the effects of the excitatory amino acid glutamate, promote entry of calcium through ion channel pores, and are essential for normal learning and memory.¹ Prolonged excessive glutamate stimulation, however, can lead to excitotoxicity and nerve cell death.

High-affinity NMDA receptor antagonists cause unacceptable side effects in humans and have not been well tolerated in clinical trials. By contrast, memantine—a moderate- to low-affinity NMDA receptor antagonist with rapid blocking/unblocking kinetics—has been well tolerated in clinical trials. The agent is readily displaced by presynaptic stimuli to allow normal channel function, but it reduces calcium influx from chronic low-amplitude glutamate stimulation.²

Table

Memantine: Fast facts

Memantine’s voltage-dependent characteristics allow it to block low-level tonic pathologic activation of NMDA receptors caused by low glutamate concentrations. This property also allows physiologic activation of receptors after synaptic release of larger glutamate concentrations that produce membrane depolarization.² Memantine has demonstrated neuroprotection of neurons exposed to glutamate in a variety of in-vitro preparations.³

In experimental models, memantine has been shown to prolong long-term potentiation, a neurophysiologic correlate of learning and memory. Rats treated with memantine show enhanced learning recovery following entorhinal cortex lesions.³

Memantine has been shown to protect cholinergic cells in both acute and chronic animal models. It also prevents pathologic changes in the hippocampus produced by direct injection of betaamyloid protein.³ These findings suggest that memantine may improve learning and memory and may have neuroprotective properties in AD.

PHARMACOKINETICS

Memantine is absorbed completely from the GI tract and reaches maximum serum concentration in 6 to 8 hours. It is widely distributed and passes the blood-brain barrier with CSF concentrations approximately one-half those of serum levels. Dosages between 5 and 30 mg/d result in serum levels of 0.025 to 0.529 mmol. Relatively little biotransformation occurs.

The agent’s half-life ranges between 75 and 100 hours.⁴ Memantine is 10% to 45% protein bound, and 80% of circulating memantine is present as the parent compound. These kinetics justify once-daily dosing, although memantine usually is given bid.

Three metabolites have been identified, none of which exhibit NMDA receptor antagonist activity. Memantine minimally inhibits cytochrome P-450 enzymes, so interactions with drugs metabolized by these enzymes are unlikely.⁵

Memantine may potentiate the effects of barbiturates, neuroleptics, anticholinergics, L-dopa, ketamine, amantadine, dextromethorphan, and dopaminergic agonists. Concomitant use of memantine and amantadine should be avoided because the compounds are chemically related and both are NMDA antagonists. Memantine may hinder the effects of dantrolene or baclofen, so doses of these agents may need to be adjusted upward.

Memantine is eliminated almost completely via renal cation transport proteins. Drugs that use the same transport system—such as cimetidine, ranitidine, procainamide, quinine, and nicotine—may interact with memantine, possibly leading to increased plasma levels of these agents.

Hydrochlorothiazide activity is reduced by 20% when memantine is co-administered. Sodium bicarbonate, carbonic anhydrous inhibitors, and other drugs that alkalinize the urine may reduce memantine clearance and increase its serum levels.⁴

In healthy elderly volunteers with normal and reduced renal function, researchers observed a significant correlation between creatine clearance and total renal clearance of memantine, suggesting that patients with renal disease may require lower dosages.⁵

EFFICACY

In a preliminary, placebo-controlled study⁷ of patients with vascular- or Alzheimer’s-type dementia, memantine was associated with improved Clinical Global Impression of Change and Behavioral Rating Scale for Geriatric Patients scores. Mini-Mental State Examination (MMSE) scores for all patients entering the study were <10, indicating severe cognitive impairment. Global measures improved in 61 of 82 (73%) patients taking memantine, 10 mg/d, and in 38 of 84 (45%) patients taking placebo. Care dependence improved 3.1 points in the memantine group and 1.1 points in the placebo group.

Reisberg et al⁸ gave memantine, 20 mg/d, or placebo to 252 patients with AD across 28 weeks. The memantine group performed at significantly higher functional levels than the placebo group on the Alzheimer’s Disease Cooperative Study ADL Scale and the Severe Impairment Battery (SIB). The differences on the Clinical Interview-Based Impression of Change with caregiver input (CIBIC-plus) scale were nearly significant (p = 0.06). Patients entering the study had MMSE scores between 3 and 14. The magnitude of drug-placebo difference was modest (approximately 6 points on the SIB).

In a third pivotal trial, 403 patients with AD were randomly assigned to memantine, 20 mg/d, or placebo across 24 weeks. All patients were also taking the cholinesterase inhibitor donepezil, 10 mg/d.⁹ The memantine/donepezil group scored higher than the placebo/donepezil group on several scales. MMSE scores at entry ranged from 5 to 14. Drug-placebo differences were similar in magnitude to those observed in earlier studies.

TOLERABILITY

Controlled trials of memantine in patients with AD demonstrated few adverse effects.

Reisberg et al⁸ reported that 84% of memantine-group patients and 87% of the placebo group experienced adverse effects. More placebo-group than memantine-group patients (17% vs. 10%) discontinued the study because of adverse events. Agitation was the most commonly cited reason for discontinuation (7% of the placebo group and 5% of those taking memantine). No adverse event was significantly more common in the memantine group.

Tariot et al⁹ noted that confusion and headache were somewhat more common among those receiving memantine versus placebo. In other studies, symptoms possibly related to memantine included headache, akathisia, insomnia, increased motor activity, and excitement.^6,10-12

CO-ADMINISTRATION WITH CHOLINESTERASE INHIBITORS

The range of AD severity targeted by memantine overlaps that addressed by the cholinesterase inhibitors donepezil, galantamine, and rivastigmine, which are indicated for mild to moderate AD. Many patients will receive both memantine and a cholinesterase inhibitor.

Data show this combination therapy to be clinically safe. Tariot et al⁹ found no increase in adverse events when memantine was co-administered with donepezil. Post-marketing surveillance studies in Germany indicate low rates of adverse events among patients receiving a cholinesterase inhibitor and memantine.¹³ In-vitro laboratory data indicate that memantine does not affect or interact with cholinesterase inhibition.¹⁴

Memantine is not metabolized by liver enzymes. No interaction with antidepressants or antipsychotics commonly used in AD is anticipated.

CLINICAL IMPLICATIONS

Memantine, with a mechanism of action different from that of existing agents, offers a new avenue of therapeutic intervention and expands the spectrum of patients who may benefit from FDA-approved drug therapy.

Research is needed to determine whether memantine is useful in earlier stages of AD and in treating mild cognitive impairment. The role of glutamate excitotoxicity in AD also needs to be defined.

Related resources

• Alzheimer’s Association. www.alz.org
• Mendez M, Cummings JL. Dementia: a clinical approach(3rd ed). Boston: Butterworth Heinemann, 2003.

Drug brand names

• Amantadine • Symmetrel
• Cimetidine • Tagamet
• Dantrolene • Dantrium
• Donepezil • Aricept
• Galantamine • Reminyl
• Memantine • Namenda
• Procainamide • Procanbid
• Procainamide • Exelon

Disclosure

The author has received research/grant support and/or is a consultant to AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eisai Pharmaceuticals, Eli Lilly and Co., Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Novartis Pharmaceuticals Corp., and Pfizer Inc.

As America’s population ages, the need to find new treatments for Alzheimer’s disease (AD) is increasingly urgent. Agents that have reached the medical mainstream in recent years target the disease in its mild to moderate stages. Memantine recently gained FDA approval for treating moderate to severe AD.

HOW IT WORKS

Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. NMDA receptors mediate the effects of the excitatory amino acid glutamate, promote entry of calcium through ion channel pores, and are essential for normal learning and memory.¹ Prolonged excessive glutamate stimulation, however, can lead to excitotoxicity and nerve cell death.

High-affinity NMDA receptor antagonists cause unacceptable side effects in humans and have not been well tolerated in clinical trials. By contrast, memantine—a moderate- to low-affinity NMDA receptor antagonist with rapid blocking/unblocking kinetics—has been well tolerated in clinical trials. The agent is readily displaced by presynaptic stimuli to allow normal channel function, but it reduces calcium influx from chronic low-amplitude glutamate stimulation.²

Table

Memantine: Fast facts

Memantine’s voltage-dependent characteristics allow it to block low-level tonic pathologic activation of NMDA receptors caused by low glutamate concentrations. This property also allows physiologic activation of receptors after synaptic release of larger glutamate concentrations that produce membrane depolarization.² Memantine has demonstrated neuroprotection of neurons exposed to glutamate in a variety of in-vitro preparations.³

In experimental models, memantine has been shown to prolong long-term potentiation, a neurophysiologic correlate of learning and memory. Rats treated with memantine show enhanced learning recovery following entorhinal cortex lesions.³

Memantine has been shown to protect cholinergic cells in both acute and chronic animal models. It also prevents pathologic changes in the hippocampus produced by direct injection of betaamyloid protein.³ These findings suggest that memantine may improve learning and memory and may have neuroprotective properties in AD.

PHARMACOKINETICS

Memantine is absorbed completely from the GI tract and reaches maximum serum concentration in 6 to 8 hours. It is widely distributed and passes the blood-brain barrier with CSF concentrations approximately one-half those of serum levels. Dosages between 5 and 30 mg/d result in serum levels of 0.025 to 0.529 mmol. Relatively little biotransformation occurs.

The agent’s half-life ranges between 75 and 100 hours.⁴ Memantine is 10% to 45% protein bound, and 80% of circulating memantine is present as the parent compound. These kinetics justify once-daily dosing, although memantine usually is given bid.

Three metabolites have been identified, none of which exhibit NMDA receptor antagonist activity. Memantine minimally inhibits cytochrome P-450 enzymes, so interactions with drugs metabolized by these enzymes are unlikely.⁵

Memantine may potentiate the effects of barbiturates, neuroleptics, anticholinergics, L-dopa, ketamine, amantadine, dextromethorphan, and dopaminergic agonists. Concomitant use of memantine and amantadine should be avoided because the compounds are chemically related and both are NMDA antagonists. Memantine may hinder the effects of dantrolene or baclofen, so doses of these agents may need to be adjusted upward.

Memantine is eliminated almost completely via renal cation transport proteins. Drugs that use the same transport system—such as cimetidine, ranitidine, procainamide, quinine, and nicotine—may interact with memantine, possibly leading to increased plasma levels of these agents.

Hydrochlorothiazide activity is reduced by 20% when memantine is co-administered. Sodium bicarbonate, carbonic anhydrous inhibitors, and other drugs that alkalinize the urine may reduce memantine clearance and increase its serum levels.⁴

In healthy elderly volunteers with normal and reduced renal function, researchers observed a significant correlation between creatine clearance and total renal clearance of memantine, suggesting that patients with renal disease may require lower dosages.⁵

EFFICACY

In a preliminary, placebo-controlled study⁷ of patients with vascular- or Alzheimer’s-type dementia, memantine was associated with improved Clinical Global Impression of Change and Behavioral Rating Scale for Geriatric Patients scores. Mini-Mental State Examination (MMSE) scores for all patients entering the study were <10, indicating severe cognitive impairment. Global measures improved in 61 of 82 (73%) patients taking memantine, 10 mg/d, and in 38 of 84 (45%) patients taking placebo. Care dependence improved 3.1 points in the memantine group and 1.1 points in the placebo group.

Reisberg et al⁸ gave memantine, 20 mg/d, or placebo to 252 patients with AD across 28 weeks. The memantine group performed at significantly higher functional levels than the placebo group on the Alzheimer’s Disease Cooperative Study ADL Scale and the Severe Impairment Battery (SIB). The differences on the Clinical Interview-Based Impression of Change with caregiver input (CIBIC-plus) scale were nearly significant (p = 0.06). Patients entering the study had MMSE scores between 3 and 14. The magnitude of drug-placebo difference was modest (approximately 6 points on the SIB).

In a third pivotal trial, 403 patients with AD were randomly assigned to memantine, 20 mg/d, or placebo across 24 weeks. All patients were also taking the cholinesterase inhibitor donepezil, 10 mg/d.⁹ The memantine/donepezil group scored higher than the placebo/donepezil group on several scales. MMSE scores at entry ranged from 5 to 14. Drug-placebo differences were similar in magnitude to those observed in earlier studies.

TOLERABILITY

Controlled trials of memantine in patients with AD demonstrated few adverse effects.

Reisberg et al⁸ reported that 84% of memantine-group patients and 87% of the placebo group experienced adverse effects. More placebo-group than memantine-group patients (17% vs. 10%) discontinued the study because of adverse events. Agitation was the most commonly cited reason for discontinuation (7% of the placebo group and 5% of those taking memantine). No adverse event was significantly more common in the memantine group.

Tariot et al⁹ noted that confusion and headache were somewhat more common among those receiving memantine versus placebo. In other studies, symptoms possibly related to memantine included headache, akathisia, insomnia, increased motor activity, and excitement.^6,10-12

CO-ADMINISTRATION WITH CHOLINESTERASE INHIBITORS

The range of AD severity targeted by memantine overlaps that addressed by the cholinesterase inhibitors donepezil, galantamine, and rivastigmine, which are indicated for mild to moderate AD. Many patients will receive both memantine and a cholinesterase inhibitor.

Data show this combination therapy to be clinically safe. Tariot et al⁹ found no increase in adverse events when memantine was co-administered with donepezil. Post-marketing surveillance studies in Germany indicate low rates of adverse events among patients receiving a cholinesterase inhibitor and memantine.¹³ In-vitro laboratory data indicate that memantine does not affect or interact with cholinesterase inhibition.¹⁴

Memantine is not metabolized by liver enzymes. No interaction with antidepressants or antipsychotics commonly used in AD is anticipated.

CLINICAL IMPLICATIONS

Memantine, with a mechanism of action different from that of existing agents, offers a new avenue of therapeutic intervention and expands the spectrum of patients who may benefit from FDA-approved drug therapy.

Research is needed to determine whether memantine is useful in earlier stages of AD and in treating mild cognitive impairment. The role of glutamate excitotoxicity in AD also needs to be defined.

Related resources

• Alzheimer’s Association. www.alz.org
• Mendez M, Cummings JL. Dementia: a clinical approach(3rd ed). Boston: Butterworth Heinemann, 2003.

Drug brand names

• Amantadine • Symmetrel
• Cimetidine • Tagamet
• Dantrolene • Dantrium
• Donepezil • Aricept
• Galantamine • Reminyl
• Memantine • Namenda
• Procainamide • Procanbid
• Procainamide • Exelon

Disclosure

The author has received research/grant support and/or is a consultant to AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eisai Pharmaceuticals, Eli Lilly and Co., Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Novartis Pharmaceuticals Corp., and Pfizer Inc.

As America’s population ages, the need to find new treatments for Alzheimer’s disease (AD) is increasingly urgent. Agents that have reached the medical mainstream in recent years target the disease in its mild to moderate stages. Memantine recently gained FDA approval for treating moderate to severe AD.

HOW IT WORKS

Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. NMDA receptors mediate the effects of the excitatory amino acid glutamate, promote entry of calcium through ion channel pores, and are essential for normal learning and memory.¹ Prolonged excessive glutamate stimulation, however, can lead to excitotoxicity and nerve cell death.

High-affinity NMDA receptor antagonists cause unacceptable side effects in humans and have not been well tolerated in clinical trials. By contrast, memantine—a moderate- to low-affinity NMDA receptor antagonist with rapid blocking/unblocking kinetics—has been well tolerated in clinical trials. The agent is readily displaced by presynaptic stimuli to allow normal channel function, but it reduces calcium influx from chronic low-amplitude glutamate stimulation.²

Table

Memantine: Fast facts

Memantine’s voltage-dependent characteristics allow it to block low-level tonic pathologic activation of NMDA receptors caused by low glutamate concentrations. This property also allows physiologic activation of receptors after synaptic release of larger glutamate concentrations that produce membrane depolarization.² Memantine has demonstrated neuroprotection of neurons exposed to glutamate in a variety of in-vitro preparations.³

In experimental models, memantine has been shown to prolong long-term potentiation, a neurophysiologic correlate of learning and memory. Rats treated with memantine show enhanced learning recovery following entorhinal cortex lesions.³

Memantine has been shown to protect cholinergic cells in both acute and chronic animal models. It also prevents pathologic changes in the hippocampus produced by direct injection of betaamyloid protein.³ These findings suggest that memantine may improve learning and memory and may have neuroprotective properties in AD.

PHARMACOKINETICS

Memantine is absorbed completely from the GI tract and reaches maximum serum concentration in 6 to 8 hours. It is widely distributed and passes the blood-brain barrier with CSF concentrations approximately one-half those of serum levels. Dosages between 5 and 30 mg/d result in serum levels of 0.025 to 0.529 mmol. Relatively little biotransformation occurs.

The agent’s half-life ranges between 75 and 100 hours.⁴ Memantine is 10% to 45% protein bound, and 80% of circulating memantine is present as the parent compound. These kinetics justify once-daily dosing, although memantine usually is given bid.

Three metabolites have been identified, none of which exhibit NMDA receptor antagonist activity. Memantine minimally inhibits cytochrome P-450 enzymes, so interactions with drugs metabolized by these enzymes are unlikely.⁵

Memantine may potentiate the effects of barbiturates, neuroleptics, anticholinergics, L-dopa, ketamine, amantadine, dextromethorphan, and dopaminergic agonists. Concomitant use of memantine and amantadine should be avoided because the compounds are chemically related and both are NMDA antagonists. Memantine may hinder the effects of dantrolene or baclofen, so doses of these agents may need to be adjusted upward.

Memantine is eliminated almost completely via renal cation transport proteins. Drugs that use the same transport system—such as cimetidine, ranitidine, procainamide, quinine, and nicotine—may interact with memantine, possibly leading to increased plasma levels of these agents.

Hydrochlorothiazide activity is reduced by 20% when memantine is co-administered. Sodium bicarbonate, carbonic anhydrous inhibitors, and other drugs that alkalinize the urine may reduce memantine clearance and increase its serum levels.⁴

In healthy elderly volunteers with normal and reduced renal function, researchers observed a significant correlation between creatine clearance and total renal clearance of memantine, suggesting that patients with renal disease may require lower dosages.⁵

EFFICACY

In a preliminary, placebo-controlled study⁷ of patients with vascular- or Alzheimer’s-type dementia, memantine was associated with improved Clinical Global Impression of Change and Behavioral Rating Scale for Geriatric Patients scores. Mini-Mental State Examination (MMSE) scores for all patients entering the study were <10, indicating severe cognitive impairment. Global measures improved in 61 of 82 (73%) patients taking memantine, 10 mg/d, and in 38 of 84 (45%) patients taking placebo. Care dependence improved 3.1 points in the memantine group and 1.1 points in the placebo group.

Reisberg et al⁸ gave memantine, 20 mg/d, or placebo to 252 patients with AD across 28 weeks. The memantine group performed at significantly higher functional levels than the placebo group on the Alzheimer’s Disease Cooperative Study ADL Scale and the Severe Impairment Battery (SIB). The differences on the Clinical Interview-Based Impression of Change with caregiver input (CIBIC-plus) scale were nearly significant (p = 0.06). Patients entering the study had MMSE scores between 3 and 14. The magnitude of drug-placebo difference was modest (approximately 6 points on the SIB).

In a third pivotal trial, 403 patients with AD were randomly assigned to memantine, 20 mg/d, or placebo across 24 weeks. All patients were also taking the cholinesterase inhibitor donepezil, 10 mg/d.⁹ The memantine/donepezil group scored higher than the placebo/donepezil group on several scales. MMSE scores at entry ranged from 5 to 14. Drug-placebo differences were similar in magnitude to those observed in earlier studies.

TOLERABILITY

Controlled trials of memantine in patients with AD demonstrated few adverse effects.

Reisberg et al⁸ reported that 84% of memantine-group patients and 87% of the placebo group experienced adverse effects. More placebo-group than memantine-group patients (17% vs. 10%) discontinued the study because of adverse events. Agitation was the most commonly cited reason for discontinuation (7% of the placebo group and 5% of those taking memantine). No adverse event was significantly more common in the memantine group.

Tariot et al⁹ noted that confusion and headache were somewhat more common among those receiving memantine versus placebo. In other studies, symptoms possibly related to memantine included headache, akathisia, insomnia, increased motor activity, and excitement.^6,10-12

CO-ADMINISTRATION WITH CHOLINESTERASE INHIBITORS

The range of AD severity targeted by memantine overlaps that addressed by the cholinesterase inhibitors donepezil, galantamine, and rivastigmine, which are indicated for mild to moderate AD. Many patients will receive both memantine and a cholinesterase inhibitor.

Data show this combination therapy to be clinically safe. Tariot et al⁹ found no increase in adverse events when memantine was co-administered with donepezil. Post-marketing surveillance studies in Germany indicate low rates of adverse events among patients receiving a cholinesterase inhibitor and memantine.¹³ In-vitro laboratory data indicate that memantine does not affect or interact with cholinesterase inhibition.¹⁴

Memantine is not metabolized by liver enzymes. No interaction with antidepressants or antipsychotics commonly used in AD is anticipated.

CLINICAL IMPLICATIONS

Memantine, with a mechanism of action different from that of existing agents, offers a new avenue of therapeutic intervention and expands the spectrum of patients who may benefit from FDA-approved drug therapy.

Research is needed to determine whether memantine is useful in earlier stages of AD and in treating mild cognitive impairment. The role of glutamate excitotoxicity in AD also needs to be defined.

Related resources

• Alzheimer’s Association. www.alz.org
• Mendez M, Cummings JL. Dementia: a clinical approach(3rd ed). Boston: Butterworth Heinemann, 2003.

Drug brand names

• Amantadine • Symmetrel
• Cimetidine • Tagamet
• Dantrolene • Dantrium
• Donepezil • Aricept
• Galantamine • Reminyl
• Memantine • Namenda
• Procainamide • Procanbid
• Procainamide • Exelon

Disclosure

The author has received research/grant support and/or is a consultant to AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eisai Pharmaceuticals, Eli Lilly and Co., Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Novartis Pharmaceuticals Corp., and Pfizer Inc.

Compared with other psychiatric diagnoses, eating disorders are relatively new. Bulimia nervosa was first described as a distinct syndrome in 1979, ^{Update on Eating Disorders.” In part 1 Harrison G. Pope, Jr., MD, and James I. Hudson, MD, ScD, of Harvard Medical School describe how to avoid undertreating bulimia nervosa. Future issues will feature insights on:}

• anorexia nervosa by Katherine A. Halmi, MD, Weill Medical College of Cornell University
• binge eating by Susan L. McElroy, MD, Renu Kotwal, MD, and Rakesh M. Kaneria, MD, University of Cincinnati College of Medicine.

Rigorous clinical research by these experts and others has helped weed out unsubstantiated theories while providing empiric evidence of eating disorders’ biological and psychological roots. This series updates the evidence for choosing medications and psychotherapies that have shown the greatest therapeutic promise.

Compared with other psychiatric diagnoses, eating disorders are relatively new. Bulimia nervosa was first described as a distinct syndrome in 1979, ^{Update on Eating Disorders.” In part 1 Harrison G. Pope, Jr., MD, and James I. Hudson, MD, ScD, of Harvard Medical School describe how to avoid undertreating bulimia nervosa. Future issues will feature insights on:}

• anorexia nervosa by Katherine A. Halmi, MD, Weill Medical College of Cornell University
• binge eating by Susan L. McElroy, MD, Renu Kotwal, MD, and Rakesh M. Kaneria, MD, University of Cincinnati College of Medicine.

Rigorous clinical research by these experts and others has helped weed out unsubstantiated theories while providing empiric evidence of eating disorders’ biological and psychological roots. This series updates the evidence for choosing medications and psychotherapies that have shown the greatest therapeutic promise.

Compared with other psychiatric diagnoses, eating disorders are relatively new. Bulimia nervosa was first described as a distinct syndrome in 1979, ^{Update on Eating Disorders.” In part 1 Harrison G. Pope, Jr., MD, and James I. Hudson, MD, ScD, of Harvard Medical School describe how to avoid undertreating bulimia nervosa. Future issues will feature insights on:}

• anorexia nervosa by Katherine A. Halmi, MD, Weill Medical College of Cornell University
• binge eating by Susan L. McElroy, MD, Renu Kotwal, MD, and Rakesh M. Kaneria, MD, University of Cincinnati College of Medicine.

Rigorous clinical research by these experts and others has helped weed out unsubstantiated theories while providing empiric evidence of eating disorders’ biological and psychological roots. This series updates the evidence for choosing medications and psychotherapies that have shown the greatest therapeutic promise.

Thousands of scientific papers have been written about bulimia, but not all patients receive effective treatments that produce remission.

To set the record straight and help psychiatrists avoid undertreating bulimia, this article discusses:

• evidence for using antidepressants, even when patients are not “depressed”
• merits of psychotherapies, including those shown to work and those that can harm
• augmentation therapies that can help increase response from partial to full remission.

Initial evaluation

Diagnosis. Bulimia nervosa is characterized by eating binges, followed by purging behaviors such as self-induced vomiting or laxative abuse^1,2 (Table 1). It affects 1% to 3% of adolescent girls and young women and occurs in women 5 to 10 times more often than in men.

Bulimia is often persistent. About one-half of bulimic patients—including those who have been treated—continue to show eating disorder features on long-term follow-up.^3,4

Psychiatric comorbidity. Most bulimic patients report a history of other psychiatric disorders, especially major depressive and bipolar disorders and anxiety disorders such as panic disorder, social phobia, and obsessive-compulsive disorder (OCD).⁵ Because these psychiatric comorbidities may occur before, during, or after bulimia nervosa, one cannot assume that mood or anxiety disorders are a cause or consequence of bulimia. Instead, bulimia nervosa, mood disorders, and anxiety disorders may be different expressions of a shared etiologic abnormality.

Table 1

DSM-IV-TR diagnostic criteria for bulimia nervosa

Evidence supporting this hypothesis comes from studies showing that these disorders:

• respond to several chemically unrelated families of antidepressants^6,7
• frequently co-occur in individual patients^5,7
• frequently co-aggregate in families.^7-9

We have published this evidence^6,7 and proposed that bulimia nervosa may be one form of a larger underlying disorder, which we termed “affective spectrum disorder.”

Antidepressants are often rapidly effective in treating bulimic symptoms,¹⁰ regardless of whether patients exhibit depressive symptoms. Thus, there is no reason to withhold antidepressant therapy simply because a bulimic patient is not depressed. The term “antidepressant” may be a misnomer; these drugs are effective for numerous conditions, of which depression is only one.

Anorexic symptoms. Co-occurring depressive or anxiety disorders in a bulimic patient will not greatly alter treatment. The antidepressants and psychotherapies typically used to treat bulimia are often equally effective for affective disorders. Co-occurring anorexia nervosa, however, is a more serious concern.

Bulimic patients often display a history of anorexia nervosa; in many cases, the patient develops anorexia nervosa as a teenager and then progresses to bulimia nervosa across several years. Her prognosis is much better if her weight normalizes with the shift to bulimia nervosa, than if her weight remains well below normal for her height. It is unclear why medications and psychotherapy are much less effective in bulimic patients with anorexic symptoms than in those with bulimia alone. Watch for further details on anorexia nervosa as this series continues in future issues of.

Medical considerations. Potential medical complications—mostly consequences of vomiting or laxative use—are important to consider when you assess a bulimic patient:¹

• The acid in vomitus may gradually erode tooth enamel, requiring dental consultation.
• Vomitus may inflame salivary gland ducts, though the swelling is usually benign.
• Frequent vomiting may result in hypokalemia and alkalosis, although aggressive medical treatment usually is not needed.

Ask about ipecac use. To induce vomiting, some patients may abuse ipecac syrup, which can cause cardiomyopathy.¹¹

Inpatient or outpatient? Unless the bulimic patient displays severe and medically dangerous anorexic symptoms, she can usually be treated as an outpatient. However, evaluate her carefully for suicidal ideation—which is not uncommon in bulimia nervosa—and consider inpatient treatment if necessary.

Medication vs. psychotherapy

The relative merits of medication versus psychotherapy in treating bulimia nervosa continue to be debated. The Cochrane Database of Systematic Reviews includes meta-analyses of both drug therapy¹² and psychotherapy¹³ for bulimia nervosa. The 2001 drug therapy review found that “the use of a single antidepressant agent was clinically effective,” with no one drug clearly superior to another. Notably, this review was published before recent findings on topiramate.

The corresponding 2002 review of psychotherapy concludes—somewhat more cautiously—that “there is a small body of evidence for the efficacy of cognitive-behavior therapy in bulimia nervosa and similar syndromes, but the quality of trials is very variable and sample sizes are often small.”

In bulimia nervosa and other psychiatric disorders, comparing psychotherapy with drug therapy is hazardous because several factors bias the comparison in favor of psychotherapy. These factors include an expectational effect, a responsibility effect, and differential generalizability of study results.

Expectational effect. Patients in clinical trials are aware that they are receiving psychotherapy and, presumably, that study investigators hope to demonstrate its efficacy. This might account for much of psychotherapy’s apparent effect, as even placebos can produce 30% to 50% improvement in bulimia.¹⁴

Responsibility effect. If a patient fails to improve in a drug study, she will conclude that the drug has failed. But if she fails to improve in a psychotherapy study, she may conclude that she has failed. Because psychological treatments generally require patients to work in therapy, the patient may feel partially responsible for the outcome. Thus, to avoid cognitive dissonance, she may consciously or unconsciously exaggerate her improvement, both in her own mind and when reporting to treaters.

Differential generalizability. Psychological study protocols, such as administering several months of a behavioral treatment, usually mimic clinical practice fairly well. This is not the case with drug study protocols.

No responsible clinician would inflexibly administer a single dosage of a single drug for a fixed period to every bulimic patient and then declare failure for all nonresponders, as is done in study protocols. In practice, the clinician can offer nonresponders augmentation strategies and additional drug trials. Thus, calculations of bulimia response rates in drug studies substantially understate response to drug therapy in clinical practice.

Table 2

How effective are medications in treating bulimia nervosa?

One also might note that psychological study findings have not “sold” well in the clinical practice marketplace. For example, in a recent survey of more than 220 bulimic women treated with psychotherapy, only 6.9% said they received a full course of cognitive behavioral therapy (CBT)¹⁴ —despite two decades of evidence of its efficacy. By contrast, untested, inefficacious, and possibly harmful psychotherapies for bulimia—including recovered-memory therapy—appear to be thriving.

Recommendation. Interpret with caution any head-to-head comparisons of psychological versus drug therapies—especially when clinical practice recommendations are made. Certain psychological therapies provided by specifically-trained individuals likely do help patients with bulimia nervosa. However, biases inherent to the studies may inflate psychological therapies’ efficacy when compared with that of drug therapy.

Therefore, for a psychiatrist who does not specialize in eating disorders to offer exclusively psychological therapy to a bulimic patient—while withholding or postponing drug therapy—may now be a questionable practice.

Choosing drug therapies

Although consensus is lacking on an optimal treatment trial sequence for bulimia nervosa, we suggest a rational approach based on the evidence and our experience (Algorithm).

First-line antidepressants. A selective serotonin reuptake inhibitor (SSRI) trial is usually the first choice (Table 2), and some data suggest that higher-than-usual dosages may be required. For example, in a large multicenter trial of fluoxetine in bulimia nervosa, 60 mg/d was considerably more effective than 20 mg/d for reducing binge eating behavior and vomiting frequency.¹⁵

Based on our observations, however, we believe that noncompliance or irregular compliance may account for this difference in response. Bulimic patients’ impulsive and obsessional behavior may keep them from taking their medications as prescribed. The higher fluoxetine dosage may therefore have been more effective simply because it ensured adequate plasma levels, even when patients missed or forgot multiple doses.

Augmenting agents. A first antidepressant trial rarely leads to complete remission of bulimic symptoms. This is not a serious concern, however, because many other options are available.

Liothyronine. Partial responders to SSRIs often become complete responders when we add a 10-day trial of liothyronine (T3), 25 μg/d. If this fails, we may try augmenting with lithium carbonate, although bulimic patients are often afraid of weight gain or lithium’s other side effects.

Topiramate. A newer augmentation strategy is to add the anticonvulsant topiramate. Used alone, topiramate demonstrated effectiveness for bulimia nervosa in one placebo-controlled, double-blind trial.¹⁶

Adding topiramate to an antidepressant regimen will likely reduce any remaining bulimic symptoms. In addition, topiramate often produces weight loss—a side effect that bulimic patients usually welcome. It remains unclear whether topiramate’s weight-loss effects might pose a hazard in patients with simultaneous bulimic and anorexic symptoms.

Other antidepressants. If the above strategies fail, other antidepressant options include venlafaxine, tricyclics, and monoamine oxidase inhibitors. Bupropion is not recommended in bulimia nervosa; one trial¹⁷ of this agent resulted in a much higher rate of grand mal seizures in bulimic patients than in patients taking bupropion for depression.

In bulimic patients with concomitant bipolar disorder, the anticonvulsants carbamazepine and valproate often reduce affective and bulimic symptoms. By contrast, the anticonvulsant phenytoin—once thought to be useful in bulimia nervosa¹⁰ —offers little benefit for either bulimic or affective symptoms.

Persistence is important when initial medication trials fail. One unblinded study followed 36 bulimic patients 9 to 19 months after they completed a controlled study with trazodone.¹⁸ Of the 26 patients who tried a second or third antidepressant, 17 (65%) achieved remission of bulimia on follow-up. Of the 10 patients who declined a second or third trial, only 1 (10%) attained remission.

Notably, these study results were obtained before the SSRIs and other newer antidepressants or topiramate became available. Cooperative patients using present-day medications might be able to achieve remission rates that exceed 65%.

Algorithm Proposed treatment approach to bulimia nervosa

How effective are psychotherapies in treating bulimia nervosa?

Psychotherapy

Cognitive-behavioral therapy. CBT—given either individually or in groups—is the most effective psychotherapy for bulimia (Table 3).¹⁹ CBT typically involves 3 to 6 months of helping the patient focus on her bulimic behaviors and on specific attitudes—such as unrealistic preoccupations with being “too fat”—that perpetuate the behaviors.

In practice, unfortunately, few bulimic patients are offered CBT, perhaps because few clinicians are trained in the specific approach used for bulimia nervosa.¹⁹ If you are not trained in using CBT for bulimia and do not have access to colleagues who offer this treatment, you may begin with medication plus simple behavioral treatments, such as:

• offering supportive therapy in the office
• referring patients to self-help groups for persons with eating disorders.

If this strategy fails, encourage patients to consider CBT—even if they must travel some distance to obtain it.

Other specialized psychotherapies. Dialectical behavior therapy and interpersonal psychotherapy appear to be effective in bulimia. Again, however, clinicians who lack training in these techniques or access to local experts may be unable to offer them. Psychodynamic therapy does not appear to offer greater benefit in bulimia nervosa than ordinary supportive counseling.

Dubious therapies. One psychodynamic approach—regrettably still practiced—is “recovered memory therapy.” Therapists who use it claim that childhood sexual abuse or other trauma can cause bulimic symptoms but patients have repressed the memory of these events.²⁰

No methodologically sound evidence has shown that childhood sexual abuse can cause bulimia nervosa years or decades later.²¹ Nor is there acceptable evidence that people can repress the memory of a traumatic experience.²² Therapists administering recovered memory therapy have been subjected to malpractice judgments totaling tens of millions of dollars from suits filed by patients who eventually realized that so-called “recovered” memories were false.²³

Another dubious therapy—eye movement desensitization and reprocessing (EMDR)—also may involve attempts to “recover” memories of putative traumatic events.²⁴ No methodologically sound evidence has shown that EMDR is effective in bulimic patients, and the technique’s theoretical basis is questionable.^24,25

Related resources

• Mental Health Net/Eating disorders. http://eatingdisorders.mentalhelp.net
• National Association of Anorexia Nervosa and Associated Disorders (ANAD). www.altrue.net/site/anadweb/
• Association for Advancement of Behavior Therapy. www.aabt.org

Drug brand names

• Bupropion • Wellbutrin
• Citalopram • Celexa
• Desipramine • Norpramin
• Fluoxetine • Prozac
• Lithium • Lithobid, Eskalith
• Nortriptyline • Pamelor, Aventyl
• Sertraline • Zoloft
• Topiramate • Topamax
• Trazodone • Desyrel
• Liothyronine • Cytomel
• Venlafaxine • Effexor

Disclosure

Dr. Pope receives research support from Ortho-McNeil Pharmaceuticals and is a consultant to Solvay Pharmaceuticals and Auxilium Pharmaceuticals.

Dr. Hudson receives research support from and is a consultant to Eli Lilly & Co. and Ortho-McNeil Pharmaceuticals.

Thousands of scientific papers have been written about bulimia, but not all patients receive effective treatments that produce remission.

To set the record straight and help psychiatrists avoid undertreating bulimia, this article discusses:

• evidence for using antidepressants, even when patients are not “depressed”
• merits of psychotherapies, including those shown to work and those that can harm
• augmentation therapies that can help increase response from partial to full remission.

Initial evaluation

Diagnosis. Bulimia nervosa is characterized by eating binges, followed by purging behaviors such as self-induced vomiting or laxative abuse^1,2 (Table 1). It affects 1% to 3% of adolescent girls and young women and occurs in women 5 to 10 times more often than in men.

Bulimia is often persistent. About one-half of bulimic patients—including those who have been treated—continue to show eating disorder features on long-term follow-up.^3,4

Psychiatric comorbidity. Most bulimic patients report a history of other psychiatric disorders, especially major depressive and bipolar disorders and anxiety disorders such as panic disorder, social phobia, and obsessive-compulsive disorder (OCD).⁵ Because these psychiatric comorbidities may occur before, during, or after bulimia nervosa, one cannot assume that mood or anxiety disorders are a cause or consequence of bulimia. Instead, bulimia nervosa, mood disorders, and anxiety disorders may be different expressions of a shared etiologic abnormality.

Table 1

DSM-IV-TR diagnostic criteria for bulimia nervosa

Evidence supporting this hypothesis comes from studies showing that these disorders:

• respond to several chemically unrelated families of antidepressants^6,7
• frequently co-occur in individual patients^5,7
• frequently co-aggregate in families.^7-9

We have published this evidence^6,7 and proposed that bulimia nervosa may be one form of a larger underlying disorder, which we termed “affective spectrum disorder.”

Antidepressants are often rapidly effective in treating bulimic symptoms,¹⁰ regardless of whether patients exhibit depressive symptoms. Thus, there is no reason to withhold antidepressant therapy simply because a bulimic patient is not depressed. The term “antidepressant” may be a misnomer; these drugs are effective for numerous conditions, of which depression is only one.

Anorexic symptoms. Co-occurring depressive or anxiety disorders in a bulimic patient will not greatly alter treatment. The antidepressants and psychotherapies typically used to treat bulimia are often equally effective for affective disorders. Co-occurring anorexia nervosa, however, is a more serious concern.

Bulimic patients often display a history of anorexia nervosa; in many cases, the patient develops anorexia nervosa as a teenager and then progresses to bulimia nervosa across several years. Her prognosis is much better if her weight normalizes with the shift to bulimia nervosa, than if her weight remains well below normal for her height. It is unclear why medications and psychotherapy are much less effective in bulimic patients with anorexic symptoms than in those with bulimia alone. Watch for further details on anorexia nervosa as this series continues in future issues of.

Medical considerations. Potential medical complications—mostly consequences of vomiting or laxative use—are important to consider when you assess a bulimic patient:¹

• The acid in vomitus may gradually erode tooth enamel, requiring dental consultation.
• Vomitus may inflame salivary gland ducts, though the swelling is usually benign.
• Frequent vomiting may result in hypokalemia and alkalosis, although aggressive medical treatment usually is not needed.

Ask about ipecac use. To induce vomiting, some patients may abuse ipecac syrup, which can cause cardiomyopathy.¹¹

Inpatient or outpatient? Unless the bulimic patient displays severe and medically dangerous anorexic symptoms, she can usually be treated as an outpatient. However, evaluate her carefully for suicidal ideation—which is not uncommon in bulimia nervosa—and consider inpatient treatment if necessary.

Medication vs. psychotherapy

The relative merits of medication versus psychotherapy in treating bulimia nervosa continue to be debated. The Cochrane Database of Systematic Reviews includes meta-analyses of both drug therapy¹² and psychotherapy¹³ for bulimia nervosa. The 2001 drug therapy review found that “the use of a single antidepressant agent was clinically effective,” with no one drug clearly superior to another. Notably, this review was published before recent findings on topiramate.

The corresponding 2002 review of psychotherapy concludes—somewhat more cautiously—that “there is a small body of evidence for the efficacy of cognitive-behavior therapy in bulimia nervosa and similar syndromes, but the quality of trials is very variable and sample sizes are often small.”

In bulimia nervosa and other psychiatric disorders, comparing psychotherapy with drug therapy is hazardous because several factors bias the comparison in favor of psychotherapy. These factors include an expectational effect, a responsibility effect, and differential generalizability of study results.

Expectational effect. Patients in clinical trials are aware that they are receiving psychotherapy and, presumably, that study investigators hope to demonstrate its efficacy. This might account for much of psychotherapy’s apparent effect, as even placebos can produce 30% to 50% improvement in bulimia.¹⁴

Responsibility effect. If a patient fails to improve in a drug study, she will conclude that the drug has failed. But if she fails to improve in a psychotherapy study, she may conclude that she has failed. Because psychological treatments generally require patients to work in therapy, the patient may feel partially responsible for the outcome. Thus, to avoid cognitive dissonance, she may consciously or unconsciously exaggerate her improvement, both in her own mind and when reporting to treaters.

Differential generalizability. Psychological study protocols, such as administering several months of a behavioral treatment, usually mimic clinical practice fairly well. This is not the case with drug study protocols.

No responsible clinician would inflexibly administer a single dosage of a single drug for a fixed period to every bulimic patient and then declare failure for all nonresponders, as is done in study protocols. In practice, the clinician can offer nonresponders augmentation strategies and additional drug trials. Thus, calculations of bulimia response rates in drug studies substantially understate response to drug therapy in clinical practice.

Table 2

How effective are medications in treating bulimia nervosa?

One also might note that psychological study findings have not “sold” well in the clinical practice marketplace. For example, in a recent survey of more than 220 bulimic women treated with psychotherapy, only 6.9% said they received a full course of cognitive behavioral therapy (CBT)¹⁴ —despite two decades of evidence of its efficacy. By contrast, untested, inefficacious, and possibly harmful psychotherapies for bulimia—including recovered-memory therapy—appear to be thriving.

Recommendation. Interpret with caution any head-to-head comparisons of psychological versus drug therapies—especially when clinical practice recommendations are made. Certain psychological therapies provided by specifically-trained individuals likely do help patients with bulimia nervosa. However, biases inherent to the studies may inflate psychological therapies’ efficacy when compared with that of drug therapy.

Therefore, for a psychiatrist who does not specialize in eating disorders to offer exclusively psychological therapy to a bulimic patient—while withholding or postponing drug therapy—may now be a questionable practice.

Choosing drug therapies

Although consensus is lacking on an optimal treatment trial sequence for bulimia nervosa, we suggest a rational approach based on the evidence and our experience (Algorithm).

First-line antidepressants. A selective serotonin reuptake inhibitor (SSRI) trial is usually the first choice (Table 2), and some data suggest that higher-than-usual dosages may be required. For example, in a large multicenter trial of fluoxetine in bulimia nervosa, 60 mg/d was considerably more effective than 20 mg/d for reducing binge eating behavior and vomiting frequency.¹⁵

Based on our observations, however, we believe that noncompliance or irregular compliance may account for this difference in response. Bulimic patients’ impulsive and obsessional behavior may keep them from taking their medications as prescribed. The higher fluoxetine dosage may therefore have been more effective simply because it ensured adequate plasma levels, even when patients missed or forgot multiple doses.

Augmenting agents. A first antidepressant trial rarely leads to complete remission of bulimic symptoms. This is not a serious concern, however, because many other options are available.

Liothyronine. Partial responders to SSRIs often become complete responders when we add a 10-day trial of liothyronine (T3), 25 μg/d. If this fails, we may try augmenting with lithium carbonate, although bulimic patients are often afraid of weight gain or lithium’s other side effects.

Topiramate. A newer augmentation strategy is to add the anticonvulsant topiramate. Used alone, topiramate demonstrated effectiveness for bulimia nervosa in one placebo-controlled, double-blind trial.¹⁶

Adding topiramate to an antidepressant regimen will likely reduce any remaining bulimic symptoms. In addition, topiramate often produces weight loss—a side effect that bulimic patients usually welcome. It remains unclear whether topiramate’s weight-loss effects might pose a hazard in patients with simultaneous bulimic and anorexic symptoms.

Other antidepressants. If the above strategies fail, other antidepressant options include venlafaxine, tricyclics, and monoamine oxidase inhibitors. Bupropion is not recommended in bulimia nervosa; one trial¹⁷ of this agent resulted in a much higher rate of grand mal seizures in bulimic patients than in patients taking bupropion for depression.

In bulimic patients with concomitant bipolar disorder, the anticonvulsants carbamazepine and valproate often reduce affective and bulimic symptoms. By contrast, the anticonvulsant phenytoin—once thought to be useful in bulimia nervosa¹⁰ —offers little benefit for either bulimic or affective symptoms.

Persistence is important when initial medication trials fail. One unblinded study followed 36 bulimic patients 9 to 19 months after they completed a controlled study with trazodone.¹⁸ Of the 26 patients who tried a second or third antidepressant, 17 (65%) achieved remission of bulimia on follow-up. Of the 10 patients who declined a second or third trial, only 1 (10%) attained remission.

Notably, these study results were obtained before the SSRIs and other newer antidepressants or topiramate became available. Cooperative patients using present-day medications might be able to achieve remission rates that exceed 65%.

Algorithm Proposed treatment approach to bulimia nervosa

How effective are psychotherapies in treating bulimia nervosa?

Psychotherapy

Cognitive-behavioral therapy. CBT—given either individually or in groups—is the most effective psychotherapy for bulimia (Table 3).¹⁹ CBT typically involves 3 to 6 months of helping the patient focus on her bulimic behaviors and on specific attitudes—such as unrealistic preoccupations with being “too fat”—that perpetuate the behaviors.

In practice, unfortunately, few bulimic patients are offered CBT, perhaps because few clinicians are trained in the specific approach used for bulimia nervosa.¹⁹ If you are not trained in using CBT for bulimia and do not have access to colleagues who offer this treatment, you may begin with medication plus simple behavioral treatments, such as:

• offering supportive therapy in the office
• referring patients to self-help groups for persons with eating disorders.

If this strategy fails, encourage patients to consider CBT—even if they must travel some distance to obtain it.

Other specialized psychotherapies. Dialectical behavior therapy and interpersonal psychotherapy appear to be effective in bulimia. Again, however, clinicians who lack training in these techniques or access to local experts may be unable to offer them. Psychodynamic therapy does not appear to offer greater benefit in bulimia nervosa than ordinary supportive counseling.

Dubious therapies. One psychodynamic approach—regrettably still practiced—is “recovered memory therapy.” Therapists who use it claim that childhood sexual abuse or other trauma can cause bulimic symptoms but patients have repressed the memory of these events.²⁰

No methodologically sound evidence has shown that childhood sexual abuse can cause bulimia nervosa years or decades later.²¹ Nor is there acceptable evidence that people can repress the memory of a traumatic experience.²² Therapists administering recovered memory therapy have been subjected to malpractice judgments totaling tens of millions of dollars from suits filed by patients who eventually realized that so-called “recovered” memories were false.²³

Another dubious therapy—eye movement desensitization and reprocessing (EMDR)—also may involve attempts to “recover” memories of putative traumatic events.²⁴ No methodologically sound evidence has shown that EMDR is effective in bulimic patients, and the technique’s theoretical basis is questionable.^24,25

Related resources

• Mental Health Net/Eating disorders. http://eatingdisorders.mentalhelp.net
• National Association of Anorexia Nervosa and Associated Disorders (ANAD). www.altrue.net/site/anadweb/
• Association for Advancement of Behavior Therapy. www.aabt.org

Drug brand names

• Bupropion • Wellbutrin
• Citalopram • Celexa
• Desipramine • Norpramin
• Fluoxetine • Prozac
• Lithium • Lithobid, Eskalith
• Nortriptyline • Pamelor, Aventyl
• Sertraline • Zoloft
• Topiramate • Topamax
• Trazodone • Desyrel
• Liothyronine • Cytomel
• Venlafaxine • Effexor

Disclosure

Dr. Pope receives research support from Ortho-McNeil Pharmaceuticals and is a consultant to Solvay Pharmaceuticals and Auxilium Pharmaceuticals.

Dr. Hudson receives research support from and is a consultant to Eli Lilly & Co. and Ortho-McNeil Pharmaceuticals.

Thousands of scientific papers have been written about bulimia, but not all patients receive effective treatments that produce remission.

To set the record straight and help psychiatrists avoid undertreating bulimia, this article discusses:

• evidence for using antidepressants, even when patients are not “depressed”
• merits of psychotherapies, including those shown to work and those that can harm
• augmentation therapies that can help increase response from partial to full remission.

Initial evaluation

Diagnosis. Bulimia nervosa is characterized by eating binges, followed by purging behaviors such as self-induced vomiting or laxative abuse^1,2 (Table 1). It affects 1% to 3% of adolescent girls and young women and occurs in women 5 to 10 times more often than in men.

Bulimia is often persistent. About one-half of bulimic patients—including those who have been treated—continue to show eating disorder features on long-term follow-up.^3,4

Psychiatric comorbidity. Most bulimic patients report a history of other psychiatric disorders, especially major depressive and bipolar disorders and anxiety disorders such as panic disorder, social phobia, and obsessive-compulsive disorder (OCD).⁵ Because these psychiatric comorbidities may occur before, during, or after bulimia nervosa, one cannot assume that mood or anxiety disorders are a cause or consequence of bulimia. Instead, bulimia nervosa, mood disorders, and anxiety disorders may be different expressions of a shared etiologic abnormality.

Table 1

DSM-IV-TR diagnostic criteria for bulimia nervosa

Evidence supporting this hypothesis comes from studies showing that these disorders:

• respond to several chemically unrelated families of antidepressants^6,7
• frequently co-occur in individual patients^5,7
• frequently co-aggregate in families.^7-9

We have published this evidence^6,7 and proposed that bulimia nervosa may be one form of a larger underlying disorder, which we termed “affective spectrum disorder.”

Antidepressants are often rapidly effective in treating bulimic symptoms,¹⁰ regardless of whether patients exhibit depressive symptoms. Thus, there is no reason to withhold antidepressant therapy simply because a bulimic patient is not depressed. The term “antidepressant” may be a misnomer; these drugs are effective for numerous conditions, of which depression is only one.

Anorexic symptoms. Co-occurring depressive or anxiety disorders in a bulimic patient will not greatly alter treatment. The antidepressants and psychotherapies typically used to treat bulimia are often equally effective for affective disorders. Co-occurring anorexia nervosa, however, is a more serious concern.

Bulimic patients often display a history of anorexia nervosa; in many cases, the patient develops anorexia nervosa as a teenager and then progresses to bulimia nervosa across several years. Her prognosis is much better if her weight normalizes with the shift to bulimia nervosa, than if her weight remains well below normal for her height. It is unclear why medications and psychotherapy are much less effective in bulimic patients with anorexic symptoms than in those with bulimia alone. Watch for further details on anorexia nervosa as this series continues in future issues of.

Medical considerations. Potential medical complications—mostly consequences of vomiting or laxative use—are important to consider when you assess a bulimic patient:¹

• The acid in vomitus may gradually erode tooth enamel, requiring dental consultation.
• Vomitus may inflame salivary gland ducts, though the swelling is usually benign.
• Frequent vomiting may result in hypokalemia and alkalosis, although aggressive medical treatment usually is not needed.

Ask about ipecac use. To induce vomiting, some patients may abuse ipecac syrup, which can cause cardiomyopathy.¹¹

Inpatient or outpatient? Unless the bulimic patient displays severe and medically dangerous anorexic symptoms, she can usually be treated as an outpatient. However, evaluate her carefully for suicidal ideation—which is not uncommon in bulimia nervosa—and consider inpatient treatment if necessary.

Medication vs. psychotherapy

The relative merits of medication versus psychotherapy in treating bulimia nervosa continue to be debated. The Cochrane Database of Systematic Reviews includes meta-analyses of both drug therapy¹² and psychotherapy¹³ for bulimia nervosa. The 2001 drug therapy review found that “the use of a single antidepressant agent was clinically effective,” with no one drug clearly superior to another. Notably, this review was published before recent findings on topiramate.

The corresponding 2002 review of psychotherapy concludes—somewhat more cautiously—that “there is a small body of evidence for the efficacy of cognitive-behavior therapy in bulimia nervosa and similar syndromes, but the quality of trials is very variable and sample sizes are often small.”

In bulimia nervosa and other psychiatric disorders, comparing psychotherapy with drug therapy is hazardous because several factors bias the comparison in favor of psychotherapy. These factors include an expectational effect, a responsibility effect, and differential generalizability of study results.

Expectational effect. Patients in clinical trials are aware that they are receiving psychotherapy and, presumably, that study investigators hope to demonstrate its efficacy. This might account for much of psychotherapy’s apparent effect, as even placebos can produce 30% to 50% improvement in bulimia.¹⁴

Responsibility effect. If a patient fails to improve in a drug study, she will conclude that the drug has failed. But if she fails to improve in a psychotherapy study, she may conclude that she has failed. Because psychological treatments generally require patients to work in therapy, the patient may feel partially responsible for the outcome. Thus, to avoid cognitive dissonance, she may consciously or unconsciously exaggerate her improvement, both in her own mind and when reporting to treaters.

Differential generalizability. Psychological study protocols, such as administering several months of a behavioral treatment, usually mimic clinical practice fairly well. This is not the case with drug study protocols.

No responsible clinician would inflexibly administer a single dosage of a single drug for a fixed period to every bulimic patient and then declare failure for all nonresponders, as is done in study protocols. In practice, the clinician can offer nonresponders augmentation strategies and additional drug trials. Thus, calculations of bulimia response rates in drug studies substantially understate response to drug therapy in clinical practice.

Table 2

How effective are medications in treating bulimia nervosa?

One also might note that psychological study findings have not “sold” well in the clinical practice marketplace. For example, in a recent survey of more than 220 bulimic women treated with psychotherapy, only 6.9% said they received a full course of cognitive behavioral therapy (CBT)¹⁴ —despite two decades of evidence of its efficacy. By contrast, untested, inefficacious, and possibly harmful psychotherapies for bulimia—including recovered-memory therapy—appear to be thriving.

Recommendation. Interpret with caution any head-to-head comparisons of psychological versus drug therapies—especially when clinical practice recommendations are made. Certain psychological therapies provided by specifically-trained individuals likely do help patients with bulimia nervosa. However, biases inherent to the studies may inflate psychological therapies’ efficacy when compared with that of drug therapy.

Therefore, for a psychiatrist who does not specialize in eating disorders to offer exclusively psychological therapy to a bulimic patient—while withholding or postponing drug therapy—may now be a questionable practice.

Choosing drug therapies

Although consensus is lacking on an optimal treatment trial sequence for bulimia nervosa, we suggest a rational approach based on the evidence and our experience (Algorithm).

First-line antidepressants. A selective serotonin reuptake inhibitor (SSRI) trial is usually the first choice (Table 2), and some data suggest that higher-than-usual dosages may be required. For example, in a large multicenter trial of fluoxetine in bulimia nervosa, 60 mg/d was considerably more effective than 20 mg/d for reducing binge eating behavior and vomiting frequency.¹⁵

Based on our observations, however, we believe that noncompliance or irregular compliance may account for this difference in response. Bulimic patients’ impulsive and obsessional behavior may keep them from taking their medications as prescribed. The higher fluoxetine dosage may therefore have been more effective simply because it ensured adequate plasma levels, even when patients missed or forgot multiple doses.

Augmenting agents. A first antidepressant trial rarely leads to complete remission of bulimic symptoms. This is not a serious concern, however, because many other options are available.

Liothyronine. Partial responders to SSRIs often become complete responders when we add a 10-day trial of liothyronine (T3), 25 μg/d. If this fails, we may try augmenting with lithium carbonate, although bulimic patients are often afraid of weight gain or lithium’s other side effects.

Topiramate. A newer augmentation strategy is to add the anticonvulsant topiramate. Used alone, topiramate demonstrated effectiveness for bulimia nervosa in one placebo-controlled, double-blind trial.¹⁶

Adding topiramate to an antidepressant regimen will likely reduce any remaining bulimic symptoms. In addition, topiramate often produces weight loss—a side effect that bulimic patients usually welcome. It remains unclear whether topiramate’s weight-loss effects might pose a hazard in patients with simultaneous bulimic and anorexic symptoms.

Other antidepressants. If the above strategies fail, other antidepressant options include venlafaxine, tricyclics, and monoamine oxidase inhibitors. Bupropion is not recommended in bulimia nervosa; one trial¹⁷ of this agent resulted in a much higher rate of grand mal seizures in bulimic patients than in patients taking bupropion for depression.

In bulimic patients with concomitant bipolar disorder, the anticonvulsants carbamazepine and valproate often reduce affective and bulimic symptoms. By contrast, the anticonvulsant phenytoin—once thought to be useful in bulimia nervosa¹⁰ —offers little benefit for either bulimic or affective symptoms.

Persistence is important when initial medication trials fail. One unblinded study followed 36 bulimic patients 9 to 19 months after they completed a controlled study with trazodone.¹⁸ Of the 26 patients who tried a second or third antidepressant, 17 (65%) achieved remission of bulimia on follow-up. Of the 10 patients who declined a second or third trial, only 1 (10%) attained remission.

Notably, these study results were obtained before the SSRIs and other newer antidepressants or topiramate became available. Cooperative patients using present-day medications might be able to achieve remission rates that exceed 65%.

Algorithm Proposed treatment approach to bulimia nervosa

How effective are psychotherapies in treating bulimia nervosa?

Psychotherapy

Cognitive-behavioral therapy. CBT—given either individually or in groups—is the most effective psychotherapy for bulimia (Table 3).¹⁹ CBT typically involves 3 to 6 months of helping the patient focus on her bulimic behaviors and on specific attitudes—such as unrealistic preoccupations with being “too fat”—that perpetuate the behaviors.

In practice, unfortunately, few bulimic patients are offered CBT, perhaps because few clinicians are trained in the specific approach used for bulimia nervosa.¹⁹ If you are not trained in using CBT for bulimia and do not have access to colleagues who offer this treatment, you may begin with medication plus simple behavioral treatments, such as:

• offering supportive therapy in the office
• referring patients to self-help groups for persons with eating disorders.

If this strategy fails, encourage patients to consider CBT—even if they must travel some distance to obtain it.

Other specialized psychotherapies. Dialectical behavior therapy and interpersonal psychotherapy appear to be effective in bulimia. Again, however, clinicians who lack training in these techniques or access to local experts may be unable to offer them. Psychodynamic therapy does not appear to offer greater benefit in bulimia nervosa than ordinary supportive counseling.

Dubious therapies. One psychodynamic approach—regrettably still practiced—is “recovered memory therapy.” Therapists who use it claim that childhood sexual abuse or other trauma can cause bulimic symptoms but patients have repressed the memory of these events.²⁰

No methodologically sound evidence has shown that childhood sexual abuse can cause bulimia nervosa years or decades later.²¹ Nor is there acceptable evidence that people can repress the memory of a traumatic experience.²² Therapists administering recovered memory therapy have been subjected to malpractice judgments totaling tens of millions of dollars from suits filed by patients who eventually realized that so-called “recovered” memories were false.²³

Another dubious therapy—eye movement desensitization and reprocessing (EMDR)—also may involve attempts to “recover” memories of putative traumatic events.²⁴ No methodologically sound evidence has shown that EMDR is effective in bulimic patients, and the technique’s theoretical basis is questionable.^24,25

Related resources

• Mental Health Net/Eating disorders. http://eatingdisorders.mentalhelp.net
• National Association of Anorexia Nervosa and Associated Disorders (ANAD). www.altrue.net/site/anadweb/
• Association for Advancement of Behavior Therapy. www.aabt.org

Drug brand names

• Bupropion • Wellbutrin
• Citalopram • Celexa
• Desipramine • Norpramin
• Fluoxetine • Prozac
• Lithium • Lithobid, Eskalith
• Nortriptyline • Pamelor, Aventyl
• Sertraline • Zoloft
• Topiramate • Topamax
• Trazodone • Desyrel
• Liothyronine • Cytomel
• Venlafaxine • Effexor

Disclosure

Dr. Pope receives research support from Ortho-McNeil Pharmaceuticals and is a consultant to Solvay Pharmaceuticals and Auxilium Pharmaceuticals.

Dr. Hudson receives research support from and is a consultant to Eli Lilly & Co. and Ortho-McNeil Pharmaceuticals.