Symptoms of obstructive sleep apnea (OSA) often mimic psychopathology. Because of this, patients with OSA who exhibit these symptoms often are misdiagnosed as having a psychiatric disorder.

Consider OSA in the differential diagnosis of:

• depression. Sleep-disordered breathing is five times more prevalent in adults and children with depression than in nondepressed patients. Psychotic features also positively correlate with OSA.¹
• anxiety. Physiologic and hormonal changes associated with OSA can cause panic attacks.
• attention-deficit/hyperactivity disorder (ADHD). Attention, concentration, and vigilance are often impaired in adults and children with OSA. Up to one-third of children with frequent, loud snoring display inattention and hyperactivity.²
• memory impairment. Deficits in working and long-term episodic memory are common in OSA.
• executive dysfunction. Patients with OSA often cannot sustain an organized, goal-directed, flexible approach to problem solving.
• erectile dysfunction. Pathologic processes activated by OSA may predispose men to impaired erectile function.³
• School phobia. Poor academic functioning is common in children with OSA. These children resist going to school because of a resultant loss of self-esteem. Excessive daytime sleepiness also contributes to poor academic performance.²
• Behavioral problems in children. Sleep deprivation often manifests as irritability and oppositional behavior.

Disturbances in intellectual and executive functioning are strongly correlated with hypoxemia. Deficits in vigilance, alertness, and memory correlate with measures of sleep fragmentation.⁴

When to suspect sleep apnea

Refer patients to a pulmonologist, ENT specialist, or sleep disorders center if the history and physical exam reveal excessive daytime sleepiness, frequent nocturia, morning headaches, nasal quality to the voice, enlarged tonsils and adenoids in children, or loud snoring or gasping sounds during sleep (consider interviewing the patient’s bed partner).

Risk factors such as family history, recessed chin, smoking, neck size >16 inches, male gender, enlarged tonsils and adenoids, and age >40 may also point to OSA. Also watch for:

• ethnicity. OSA is most prevalent among Pacific Islanders, Hispanics, and African-Americans.
• BMI >25 in adults younger than age 65. However, OSA is often missed in young people who are not obese.

Symptoms of obstructive sleep apnea (OSA) often mimic psychopathology. Because of this, patients with OSA who exhibit these symptoms often are misdiagnosed as having a psychiatric disorder.

Consider OSA in the differential diagnosis of:

• depression. Sleep-disordered breathing is five times more prevalent in adults and children with depression than in nondepressed patients. Psychotic features also positively correlate with OSA.¹
• anxiety. Physiologic and hormonal changes associated with OSA can cause panic attacks.
• attention-deficit/hyperactivity disorder (ADHD). Attention, concentration, and vigilance are often impaired in adults and children with OSA. Up to one-third of children with frequent, loud snoring display inattention and hyperactivity.²
• memory impairment. Deficits in working and long-term episodic memory are common in OSA.
• executive dysfunction. Patients with OSA often cannot sustain an organized, goal-directed, flexible approach to problem solving.
• erectile dysfunction. Pathologic processes activated by OSA may predispose men to impaired erectile function.³
• School phobia. Poor academic functioning is common in children with OSA. These children resist going to school because of a resultant loss of self-esteem. Excessive daytime sleepiness also contributes to poor academic performance.²
• Behavioral problems in children. Sleep deprivation often manifests as irritability and oppositional behavior.

Disturbances in intellectual and executive functioning are strongly correlated with hypoxemia. Deficits in vigilance, alertness, and memory correlate with measures of sleep fragmentation.⁴

When to suspect sleep apnea

Refer patients to a pulmonologist, ENT specialist, or sleep disorders center if the history and physical exam reveal excessive daytime sleepiness, frequent nocturia, morning headaches, nasal quality to the voice, enlarged tonsils and adenoids in children, or loud snoring or gasping sounds during sleep (consider interviewing the patient’s bed partner).

Risk factors such as family history, recessed chin, smoking, neck size >16 inches, male gender, enlarged tonsils and adenoids, and age >40 may also point to OSA. Also watch for:

• ethnicity. OSA is most prevalent among Pacific Islanders, Hispanics, and African-Americans.
• BMI >25 in adults younger than age 65. However, OSA is often missed in young people who are not obese.

Symptoms of obstructive sleep apnea (OSA) often mimic psychopathology. Because of this, patients with OSA who exhibit these symptoms often are misdiagnosed as having a psychiatric disorder.

Consider OSA in the differential diagnosis of:

• depression. Sleep-disordered breathing is five times more prevalent in adults and children with depression than in nondepressed patients. Psychotic features also positively correlate with OSA.¹
• anxiety. Physiologic and hormonal changes associated with OSA can cause panic attacks.
• attention-deficit/hyperactivity disorder (ADHD). Attention, concentration, and vigilance are often impaired in adults and children with OSA. Up to one-third of children with frequent, loud snoring display inattention and hyperactivity.²
• memory impairment. Deficits in working and long-term episodic memory are common in OSA.
• executive dysfunction. Patients with OSA often cannot sustain an organized, goal-directed, flexible approach to problem solving.
• erectile dysfunction. Pathologic processes activated by OSA may predispose men to impaired erectile function.³
• School phobia. Poor academic functioning is common in children with OSA. These children resist going to school because of a resultant loss of self-esteem. Excessive daytime sleepiness also contributes to poor academic performance.²
• Behavioral problems in children. Sleep deprivation often manifests as irritability and oppositional behavior.

Disturbances in intellectual and executive functioning are strongly correlated with hypoxemia. Deficits in vigilance, alertness, and memory correlate with measures of sleep fragmentation.⁴

When to suspect sleep apnea

Refer patients to a pulmonologist, ENT specialist, or sleep disorders center if the history and physical exam reveal excessive daytime sleepiness, frequent nocturia, morning headaches, nasal quality to the voice, enlarged tonsils and adenoids in children, or loud snoring or gasping sounds during sleep (consider interviewing the patient’s bed partner).

Risk factors such as family history, recessed chin, smoking, neck size >16 inches, male gender, enlarged tonsils and adenoids, and age >40 may also point to OSA. Also watch for:

• ethnicity. OSA is most prevalent among Pacific Islanders, Hispanics, and African-Americans.
• BMI >25 in adults younger than age 65. However, OSA is often missed in young people who are not obese.

Summit Directors and Editors:
Michael A. DeGeorgia, MD; Derk Krieger, MD, PhD; and Anthony Furlan, MD

Contents

Foreword
Michael DeGeorgia, MD

Historical Perspectives: Neurointensive Care

The development of neurologic intensive care
Allan H. Ropper, MD, St. Elizabeth's Medical Center and Tufts University School of Medicine, Boston, MA

Intracranial Pressure

The pathophysiology of brain edema and elevated intracranial pressure
Anthony Marmarou, PhD, Virginia Commonwealth University Medical Center, Richmond, VA

Hypertonic saline for cerebral edema and elevated intracranial pressure
José I. Suarez, MD, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH

Every breath you take: Hyperventilation and intracranial pressure
Claudia Robertson, MD, Baylor College of Medicine, Houston, TX

Multimodal monitoring in neurocritical care
Michael A. DeGeorgia, MD, The Cleveland Clinic Foundation, Cleveland, OH

Hemorrhagic Stroke

Endovascular coiling: The end of conventional neurosurgery?
Peter A. Rasmussen, MD, The Cleveland Clinic Foundation, Cleveland, OH

Fundamentals of Cricital Care

Lessons from the medical and surgical ICU
J. Javier Provencio, MD, The Cleveland Clinic Foundation, Cleveland, OH

Historical Perspectives: Cerebrovascular Disease

Cerebrovascular disease: Historical background, with an eye to the future
Louis R. Caplan, MD, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA

Acute Ischemic Stroke

Pathophysiology of acute ischemic stroke
Midori A. Yenari, MD, Stanford University, Stanford, CA

Intravenous thrombolysis for acute stroke
Joseph P. Broderick, MD, University of Cincinnati College of Medicine, Cincinnati, OH

Intra-arterial thrombolysis for acute stroke
Anthony Furlan, MD, The Cleveland Clinic Foundation, Cleveland, OH

Therapeutic hypothermia may enhance reperfusion in acute ischemic stroke
Derk W. Krieger, MD, PhD, The Cleveland Clinic Foundation, Cleveland, OH

Stem cell transplantation for stroke
Lawrence R. Wechsler, MD, University of Pittsburgh Medical School, Pittsburgh, PA

Extracranial Disease

Carotid artery disease: From knife to stent
Marc R. Mayberg, MD, The Cleveland Clinic Foundation, Cleveland, OH

Carotid stenting in high-risk patients: Design and rationale of the SAPPHIRE trial
Jay S. Yadav, MD, The Cleveland Clinic Foundation, Cleveland, OH

Intracranial Disease

Medical management of intracranial atherosclerosis: Current state of the art
Cathy A. Sila, MD, The Cleveland Clinic Foundation, Cleveland, OH

Intracranial stentings: Which patients and when?
Randall T. Higashida, MD, University of California, San Francisco, Medical Center, San Francisco, CA

Antithrombotic Therapy

Anticoagulation for stroke prevention: Yes, no, maybe
J.P. Mohr, MD, The Neurological Institute, New York, NY

Antiplatelet therapy for acute stroke: Aspirin and beyond
Cathy A. Sila, MD, The Cleveland Clinic Foundation, Cleveland, OH

Abstracts/Poster Presentations

Abstract 1: Hyponatremia-related focal cerebral edema, a mimic of worsening cerebral edema due to intracerebral hemorrhage
P. Widdes-Walsh, V. Sabharwal

Abstract 2: Suboccipital craniectomy for acute cerebellar ischemic stroke
B.R. Cohen, G.L. Bernardini, D. Friedlich, A.J. Popp

Abstract 3: The feasibility and safety of mild brain hypothermia obtained by local surface cooling in acute stroke
K. Yamada, H. Moriwaki, H. Oe, K. Miyashita, K. Nagatsuka, T. Yamawaki, H. Naritomi

Abstract 4: The Diverter, a novel permanent arterial diversion device
J. Leor, Y. Grad, O. Oz, Y. Assaf

Abstract 5: Fatal arrhythmia in an anxious patient during recovery from lateral medullary infarction
J.G. Lattore

Abstract 6: Motor, behavioral, and cognitive changes in patients with thalamic lesions
A.V. Srinivasan, B.S. Virudhagirinathan, C.U. Velmurugendran

Abstract 7: Reversal of locked-in syndrome with anticoagulation, induced hypertension, and intravenous t-PA
K.E. Wartenberg, N.S. Janjua, S.A. Mayer, P. Meyers

Abstract 8: Dantrolene reduces the threshold and gain for shivering
R. Lenhardt

Abstract 9: Predicting outcome after subarachnoid hemorrhage: Comparison of different grading systems
M. Berker, A. Deogaonkar, V. Sabharwal, P. Rasmussen, M. Mayberg, M. DeGeorgia

Abstract 10: Integrative monitoring methods in neurocricital care
A. Deogaonkar, A. Vander Kouwe, K. Horning, R. Burgess, M. DeGerogia

Summit Directors and Editors:
Michael A. DeGeorgia, MD; Derk Krieger, MD, PhD; and Anthony Furlan, MD

Contents

Foreword
Michael DeGeorgia, MD

Historical Perspectives: Neurointensive Care

The development of neurologic intensive care
Allan H. Ropper, MD, St. Elizabeth's Medical Center and Tufts University School of Medicine, Boston, MA

Intracranial Pressure

The pathophysiology of brain edema and elevated intracranial pressure
Anthony Marmarou, PhD, Virginia Commonwealth University Medical Center, Richmond, VA

Hypertonic saline for cerebral edema and elevated intracranial pressure
José I. Suarez, MD, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH

Every breath you take: Hyperventilation and intracranial pressure
Claudia Robertson, MD, Baylor College of Medicine, Houston, TX

Multimodal monitoring in neurocritical care
Michael A. DeGeorgia, MD, The Cleveland Clinic Foundation, Cleveland, OH

Hemorrhagic Stroke

Endovascular coiling: The end of conventional neurosurgery?
Peter A. Rasmussen, MD, The Cleveland Clinic Foundation, Cleveland, OH

Fundamentals of Cricital Care

Lessons from the medical and surgical ICU
J. Javier Provencio, MD, The Cleveland Clinic Foundation, Cleveland, OH

Historical Perspectives: Cerebrovascular Disease

Cerebrovascular disease: Historical background, with an eye to the future
Louis R. Caplan, MD, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA

Acute Ischemic Stroke

Pathophysiology of acute ischemic stroke
Midori A. Yenari, MD, Stanford University, Stanford, CA

Intravenous thrombolysis for acute stroke
Joseph P. Broderick, MD, University of Cincinnati College of Medicine, Cincinnati, OH

Intra-arterial thrombolysis for acute stroke
Anthony Furlan, MD, The Cleveland Clinic Foundation, Cleveland, OH

Therapeutic hypothermia may enhance reperfusion in acute ischemic stroke
Derk W. Krieger, MD, PhD, The Cleveland Clinic Foundation, Cleveland, OH

Stem cell transplantation for stroke
Lawrence R. Wechsler, MD, University of Pittsburgh Medical School, Pittsburgh, PA

Extracranial Disease

Carotid artery disease: From knife to stent
Marc R. Mayberg, MD, The Cleveland Clinic Foundation, Cleveland, OH

Carotid stenting in high-risk patients: Design and rationale of the SAPPHIRE trial
Jay S. Yadav, MD, The Cleveland Clinic Foundation, Cleveland, OH

Intracranial Disease

Medical management of intracranial atherosclerosis: Current state of the art
Cathy A. Sila, MD, The Cleveland Clinic Foundation, Cleveland, OH

Intracranial stentings: Which patients and when?
Randall T. Higashida, MD, University of California, San Francisco, Medical Center, San Francisco, CA

Antithrombotic Therapy

Anticoagulation for stroke prevention: Yes, no, maybe
J.P. Mohr, MD, The Neurological Institute, New York, NY

Antiplatelet therapy for acute stroke: Aspirin and beyond
Cathy A. Sila, MD, The Cleveland Clinic Foundation, Cleveland, OH

Abstracts/Poster Presentations

Abstract 1: Hyponatremia-related focal cerebral edema, a mimic of worsening cerebral edema due to intracerebral hemorrhage
P. Widdes-Walsh, V. Sabharwal

Abstract 2: Suboccipital craniectomy for acute cerebellar ischemic stroke
B.R. Cohen, G.L. Bernardini, D. Friedlich, A.J. Popp

Abstract 3: The feasibility and safety of mild brain hypothermia obtained by local surface cooling in acute stroke
K. Yamada, H. Moriwaki, H. Oe, K. Miyashita, K. Nagatsuka, T. Yamawaki, H. Naritomi

Abstract 4: The Diverter, a novel permanent arterial diversion device
J. Leor, Y. Grad, O. Oz, Y. Assaf

Abstract 5: Fatal arrhythmia in an anxious patient during recovery from lateral medullary infarction
J.G. Lattore

Abstract 6: Motor, behavioral, and cognitive changes in patients with thalamic lesions
A.V. Srinivasan, B.S. Virudhagirinathan, C.U. Velmurugendran

Abstract 7: Reversal of locked-in syndrome with anticoagulation, induced hypertension, and intravenous t-PA
K.E. Wartenberg, N.S. Janjua, S.A. Mayer, P. Meyers

Abstract 8: Dantrolene reduces the threshold and gain for shivering
R. Lenhardt

Abstract 9: Predicting outcome after subarachnoid hemorrhage: Comparison of different grading systems
M. Berker, A. Deogaonkar, V. Sabharwal, P. Rasmussen, M. Mayberg, M. DeGeorgia

Abstract 10: Integrative monitoring methods in neurocricital care
A. Deogaonkar, A. Vander Kouwe, K. Horning, R. Burgess, M. DeGerogia

Summit Directors and Editors:
Michael A. DeGeorgia, MD; Derk Krieger, MD, PhD; and Anthony Furlan, MD

Contents

Foreword
Michael DeGeorgia, MD

Historical Perspectives: Neurointensive Care

The development of neurologic intensive care
Allan H. Ropper, MD, St. Elizabeth's Medical Center and Tufts University School of Medicine, Boston, MA

Intracranial Pressure

The pathophysiology of brain edema and elevated intracranial pressure
Anthony Marmarou, PhD, Virginia Commonwealth University Medical Center, Richmond, VA

Hypertonic saline for cerebral edema and elevated intracranial pressure
José I. Suarez, MD, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH

Every breath you take: Hyperventilation and intracranial pressure
Claudia Robertson, MD, Baylor College of Medicine, Houston, TX

Multimodal monitoring in neurocritical care
Michael A. DeGeorgia, MD, The Cleveland Clinic Foundation, Cleveland, OH

Hemorrhagic Stroke

Endovascular coiling: The end of conventional neurosurgery?
Peter A. Rasmussen, MD, The Cleveland Clinic Foundation, Cleveland, OH

Fundamentals of Cricital Care

Lessons from the medical and surgical ICU
J. Javier Provencio, MD, The Cleveland Clinic Foundation, Cleveland, OH

Historical Perspectives: Cerebrovascular Disease

Cerebrovascular disease: Historical background, with an eye to the future
Louis R. Caplan, MD, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA

Acute Ischemic Stroke

Pathophysiology of acute ischemic stroke
Midori A. Yenari, MD, Stanford University, Stanford, CA

Intravenous thrombolysis for acute stroke
Joseph P. Broderick, MD, University of Cincinnati College of Medicine, Cincinnati, OH

Intra-arterial thrombolysis for acute stroke
Anthony Furlan, MD, The Cleveland Clinic Foundation, Cleveland, OH

Therapeutic hypothermia may enhance reperfusion in acute ischemic stroke
Derk W. Krieger, MD, PhD, The Cleveland Clinic Foundation, Cleveland, OH

Stem cell transplantation for stroke
Lawrence R. Wechsler, MD, University of Pittsburgh Medical School, Pittsburgh, PA

Extracranial Disease

Carotid artery disease: From knife to stent
Marc R. Mayberg, MD, The Cleveland Clinic Foundation, Cleveland, OH

Carotid stenting in high-risk patients: Design and rationale of the SAPPHIRE trial
Jay S. Yadav, MD, The Cleveland Clinic Foundation, Cleveland, OH

Intracranial Disease

Medical management of intracranial atherosclerosis: Current state of the art
Cathy A. Sila, MD, The Cleveland Clinic Foundation, Cleveland, OH

Intracranial stentings: Which patients and when?
Randall T. Higashida, MD, University of California, San Francisco, Medical Center, San Francisco, CA

Antithrombotic Therapy

Anticoagulation for stroke prevention: Yes, no, maybe
J.P. Mohr, MD, The Neurological Institute, New York, NY

Antiplatelet therapy for acute stroke: Aspirin and beyond
Cathy A. Sila, MD, The Cleveland Clinic Foundation, Cleveland, OH

Abstracts/Poster Presentations

Abstract 1: Hyponatremia-related focal cerebral edema, a mimic of worsening cerebral edema due to intracerebral hemorrhage
P. Widdes-Walsh, V. Sabharwal

Abstract 2: Suboccipital craniectomy for acute cerebellar ischemic stroke
B.R. Cohen, G.L. Bernardini, D. Friedlich, A.J. Popp

Abstract 3: The feasibility and safety of mild brain hypothermia obtained by local surface cooling in acute stroke
K. Yamada, H. Moriwaki, H. Oe, K. Miyashita, K. Nagatsuka, T. Yamawaki, H. Naritomi

Abstract 4: The Diverter, a novel permanent arterial diversion device
J. Leor, Y. Grad, O. Oz, Y. Assaf

Abstract 5: Fatal arrhythmia in an anxious patient during recovery from lateral medullary infarction
J.G. Lattore

Abstract 6: Motor, behavioral, and cognitive changes in patients with thalamic lesions
A.V. Srinivasan, B.S. Virudhagirinathan, C.U. Velmurugendran

Abstract 7: Reversal of locked-in syndrome with anticoagulation, induced hypertension, and intravenous t-PA
K.E. Wartenberg, N.S. Janjua, S.A. Mayer, P. Meyers

Abstract 8: Dantrolene reduces the threshold and gain for shivering
R. Lenhardt

Abstract 9: Predicting outcome after subarachnoid hemorrhage: Comparison of different grading systems
M. Berker, A. Deogaonkar, V. Sabharwal, P. Rasmussen, M. Mayberg, M. DeGeorgia

Abstract 10: Integrative monitoring methods in neurocricital care
A. Deogaonkar, A. Vander Kouwe, K. Horning, R. Burgess, M. DeGerogia

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.