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A cry for help: Treating involuntary emotional expression disorder
Mrs. R, a 68-year-old retired teacher, is referred to you for suspected mania after a closed head injury from a car accident. The referring physician reports that Mrs. R experienced mild anterograde amnesia that has resolved, but she continues to suffer from “persistent mood swings as evidenced by substantial inappropriate laughter.”
Mrs. R is not manic. Her mood is normal, with a relatively euthymic affect. When asked about her accident or injury, however, she breaks into bouts of laughter that appear to be uncontrollable and last up to several minutes. These episodes include respiratory changes that make her laughter nearly indistinguishable from crying. Mrs. R explains that the episodes occur every time she discusses the accident—regardless of her efforts to prevent them—and complains they are extremely frustrating and embarrassing. She avoids situations that might trigger the episodes.
Patients with involuntary emotional expression disorder (IEED)—a neurologic disorder that manifests as brief bouts of uncontrollable crying, laughing, or both—may appear to have bipolar disorder, schizophrenia, depression, or another psychiatric disorder. Careful evaluation, however, can distinguish IEED from other conditions. Managing the disorder requires an understanding of IEED phenomenology, including:
- neurologic conditions that result in IEED
- underlying pathology
- diagnostic criteria
- effective treatments.
Brain dysfunction alters affect
IEED was introduced as an inclusive term, replacing previous nomenclature such as pathologic laughing and crying, pseudobulbar affect, affective lability, and emotional incontinence.1
IEED can present as episodes of laughter, as in Mrs. R’s case, but more commonly manifests as bouts of crying. Other presentations include a combination of laughing and crying, but episodic outbursts of other emotions that are out of the patient’s control—such as anger—can be included in this syndrome.2 IEED episodes can lead to embarrassment, frustration, and anger that eventually can affect mood and often cause patients to avoid social interaction.3
IEED can occur in any condition that damages and affects the brain areas critical to emotional motor output (Box 1).4-6 The broad pattern of lesions that can result in IEED stems from many disease states. IEED is often observed in amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, and traumatic brain injury. It also may occur in dementia, Parkinson’s disease, and other disorders (Table 1).7
Table 1
Neurologic conditions associated with IEED
| Amyotrophic lateral sclerosis |
| Multiple sclerosis |
| Traumatic brain injury |
| Stroke |
| Alzheimer’s disease |
| Frontotemporal dementia |
| Parkinson’s disease |
| Progressive supranuclear palsy |
| Multiple systems atrophy |
| Wilson’s disease |
| Normal pressure hydrocephalus |
| Olivopontine cerebellar atrophy |
| Source: Reference 7 |
Diagnosis can be elusive
Although IEED is not included in DSM-IV-TR, recently developed diagnostic criteria can help distinguish it from other disorders (Table 2).1 As with DSM-categorized disorders, IEED must result in clinically significant distress or impairment in social or occupational function and must not be better accounted for by another disorder or caused by a physiologic substance.
The patient must present with symptoms caused by brain dysfunction from brain injury or neurodegenerative disease. Underlying brain damage might not be apparent when the patient first presents, but to our knowledge no case of idiopathic IEED has been described. If a patient presents with symptoms thought to be IEED, first determine what underlying neurologic condition is causing the symptoms and optimally manage this disorder.
Symptoms must be incongruent with or in excess of the person’s underlying mood and independent or in excess of the provoking stimulus. Inappropriateness of the emotional response is the hallmark of IEED.
Some characteristics support—but are not essential for—an IEED diagnosis:
- autonomic symptoms, such as flushing of the face and increased salivary production during episodes
- pseudobulbar signs, such as increased jaw jerk, exaggerated gag reflex, dysarthria, and dysphagia
- other emotional outbursts.
Table 2
Is it IEED? Diagnostic criteria
| Presence of brain damage |
Episodes of involuntary emotional motor output that:
|
Disorder is not:
|
| Source: Reference 1 |
Characteristics of IEED episodes
| Paroxysmal, sudden onset with rapid offset |
| Brief (up to several minutes) |
| Stereotyped across patients (may manifest in similar fashion from patient to patient) |
| Stereotyped within patients (episodes often have similar type, severity, and eliciting stimuli) |
Damage to the descending inputs to the pontomedullary area once referred to as the faciorespiratory center is most likely to result in release of bulbar function and, subsequently, involuntary emotional expression disorder (IEED). Therefore, because of the progressive upper motor neuron degeneration associated with amyotrophic lateral sclerosis (ALS), nearly 50% of ALS patients will eventually demonstrate pathological affect.4
The lesions that can result in IEED are diffuse, however, and have been described in a review of IEED neuroanatomy as including a cortico-limbic-subcortico-thalamo-ponto-cerebellar network.5 Single lesions to white matter structures—such as the internal capsule—and gray matter structures—such as the thalamus, hypothalamus, basal ganglia, cerebellum, and several cortical locations—have been associated with IEED. Bilateral lesions are more likely to produce the disorder than single lesions.
With such varied neuroanatomic substrates, predicting the underlying neurochemical pathology of IEED is difficult. Among the neurotransmitters considered in IEED pathology and treatment are serotonin, glutamate, and dopamine. The sigma-1 receptor system may also play a role.6
CASE CONTINUED: Reaching a diagnosis
After thoroughly interviewing Mrs. R, you exclude mood disorders such as depression or bipolar disorder. The paroxysmal, episodic nature of her emotional outbursts and the consistency of the eliciting stimulus, suggest IEED.
Distinguishing IEED from depression. Physicians may be quick to diagnose a patient with consistent, recurrent crying as having a depressive disorder. In IEED, the patient’s family commonly (and inappropriately) will confirm this misperception, even if the patient claims otherwise. The hallmark distinctions between depression and IEED are:
- duration of crying
- associated mood state.
Patients who suffer from MDD, however, are not excluded from an IEED diagnosis. In 1 small study, almost one-half of patients with IEED also had major depression.12 Differentiating these syndromes—even in patients who suffer from both—is important to ensure proper management and patient and family understanding of the condition. Lastly, although IEED is not a mood disorder, the embarrassment and frustration it causes can change a patient’s mood over time.
Recommended treatment
Education. In our experience, education is critical to help patients and family members understand IEED and deal with embarrassment and other normal reactions they may experience. Explain that these emotional displays are not manic or psychotic episodes but periods of motor dyscontrol caused by a neurologic condition.
Teach them to cope with IEED by:
- identifying and avoiding stimuli that provoke IEED episodes
- ignoring the episodes and continuing with usual activities.
These agents have IEED-specific therapeutic effects through a mechanism independent of their antidepressant action. In patients with IEED and depression, antidepressants may resolve IEED while depression remains refractory.2,12 Potential drawbacks include anticholinergic effects with TCAs and sexual and gastrointestinal side effects with SSRIs. Nevertheless, these agents are the optimal first-line therapy for IEED among currently available options.
Other agents. Small studies have investigated other agents, but the data are insufficient to warrant recommendations for clinical practice. One study found that the novel antidepressant mirtazapine improved symptoms in 2 patients who did not respond to SSRIs.17 In another study, levodopa therapy resulted in improvement in 10 of 25 patients.18
Among scales that measure involuntary emotional expression disorder (IEED) severity, 2 have been used in studies of IEED therapeutic efficacy (see Related Resources):12,19,20
- Pathological Laughing and Crying Scale (PLACS) developed by Robinson et al12 is an interviewer-administered, 18-item tool that has been validated in IEED patients with stroke,12 dementia,22and traumatic brain injury.23
- 7-item Center for Neurologic Study-Lability Scale (CNS-LS) is a self-report measure that has been validated in IEED patients with amyotrophic lateral sclerosis24 and multiple sclerosis.25
Although these scales have been used primarily for research, you can use them clinically to establish a baseline of IEED severity and gauge treatment efficacy. Improved scores generally correlate with successful treatment; if a patient fails to show adequate response on 1 of these scales, consider changing treatment.
A combination dextromethorphan and quinidine (DM/Q) is being evaluated for IEED. This compound has demonstrated efficacy in IEED patients with ALS19 and MS20 and is in Phase III clinical development. DM/Q is thought to be a potent activator of the sigma-1 receptor system as well as an N-methyl-D-aspartate antagonist.21
Table 4
IEED: Evidence for antidepressants
| Drug | Study design/population | Dosage | Outcome |
|---|---|---|---|
| Tricyclics | |||
| Amitriptyline | Schiffer et al;13 double-blind crossover; 12 multiple sclerosis patients | Mean: 57.8 mg/d | 8 patients showed significant improvement compared with placebo |
| Nortriptyline | Robinson et al;12 double-blind, placebo-controlled; 28 stroke patients | ≤100 mg/d | Patients receiving nortriptyline reported significantly greater improvement on PLACS at 4 and 6 weeks compared with placebo |
| Selective serotonin reuptake inhibitors | |||
| Citalopram | Anderson et al;14 double-blind, placebo-controlled crossover; 16 stroke patients | 10 to 20 mg/d | Citalopram decreased the number of daily crying episodes by ≥50% compared with placebo |
| Fluoxetine | Choi-Kwon et al;2 double-blind placebo-controlled; 152 patients | 20 mg/d | Fluoxetine significantly improved measures of IEED and anger proneness but not depression |
| Paroxetine | Müller et al;15 consecutive case series, comparison with citalopram; 26 patients with traumatic brain injury or stroke | 10 to 40 mg/d | Both paroxetine and citalopram resulted in significant improvements in measures of emotionalism |
| Sertraline | Burns et al;16 double-blind, placebo-controlled; 28 stroke patients | 50 mg/d | Patients receiving sertraline had significant improvements in measures of emotionalism |
| IEED: involuntary emotional expression disorder; PLACS: Pathological Laughing and Crying Scale | |||
CASE CONTINUED: Effective pharmacotherapy
After diagnosing IEED, you start Mrs. R on sertraline, 50 mg/d. She experiences a nearly immediate reduction in the number of daily IEED episodes. As a result, she feels more comfortable engaging in social activities.
Effective pharmacologic intervention can greatly improve patients’ quality of life.19,20 Use scales that measure IEED severity to gauge treatment effectiveness (Box 2).12,19,20,22-25 Because treatment failure is a realistic possibility,17 you may need to try a variety of agents to determine which regimen provides the greatest efficacy and therapeutic effects.
- Involuntary emotional expressive disorder (for healthcare professionals). www.ieed.org/hp.
- Pathological laughing and crying scale (PLACS). Robinson RG, Parikh RM, Lipsey JR, et al. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 1993;150:286-93.
- Center for neurologic study—lability scale (CNS-LS). Moore SR, Gresham LS, Bromberg MB, et al. A self report measure of affective lability. J Neurol Neurosurg Psychiatry 1997;63:89-93.
- Amitriptyline • Elavil, Endep
- Citalopram • Celexa
- Dextromethorphan/quinidine • Zenvia*
- Fluoxetine • Prozac
- Levodopa • Larodopa
- Mirtazapine • Remeron
- Nortriptyline • Aventyl
- Paroxetine • Paxil
- Sertraline • Zoloft
- * IN PHASE III DEVELOPMENT
Dr. Grill reports no financial relationship with any company whose products are mentioned in the article or with manufacturers of competing products.
Dr. Cummings is a consultant to Acadia Pharmaceuticals, Astellas Pharma, Avanir Pharmaceuticals, Cephalon, CoMentis, Eisai, Eli Lilly and Company, EnVivo Pharmaceuticals, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merck, Merz Pharma, Myriad, Neurochem, Novartis, Ono Pharmaceutical Co., Pfizer Inc., and sanofi-aventis. He is a speaker for Eisai, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merz Pharma, Novartis, and Pfizer Inc.
1. Cummings JL, Arciniegas DB, Brooks BR, et al. Defining and diagnosing involuntary emotional expression disorder. CNS Spectr 2006;11:1-7.
2. Choi-Kwon S, Han SW, Kwon SU, et al. Fluoxetine treatment in poststroke depression, emotional incontinence, and anger proneness: a double-blind, placebo-controlled study. Stroke 2006;37:156-61.
3. Lieberman A, Benson DF. Control of emotional expression in pseudobulbar palsy. A personal experience. Arch Neurol 1977;34:717-9.
4. Caroscio JT, Mulvihill MN, Sterling R, Abrams B. Amyotrophic lateral sclerosis. Its natural history. Neurol Clin 1987;5:1-8.
5. Arciniegas DB, Lauterbach EC, Anderson KE, et al. The differential diagnosis of pseudobulbar affect (PBA). Distinguishing PBA among disorders of mood and affect. Proceedings of a roundtable meeting. CNS Spectr 2005;10:1-14; quiz 15-16.-
6. Rabins PV, Arciniegas DB. Pathophysiology of involuntary emotional expression disorder. CNS Spectr 2007;12:17-22.
7. Arciniegas DB, Topkoff J. The neuropsychiatry of pathologic affect: an approach to evaluation and treatment. Semin Clin Neuropsychiatry 2000;5:290-306.
8. Green RL, McAllister TW, Bernat JL. A study of crying in medically and surgically hospitalized patients. Am J Psychiatry 1987;144:442-7.
9. Dark FL, McGrath JJ, Ron MA. Pathological laughing and crying. Aust N Z J Psychiatry 1996;30:472-9.
10. Wilson S. Some problems in neurology. II. Pathological laughing and crying. J Neurol Psychopathol 1924;16:299-333.
11. Diagnostic and statistical manual of mental disorders. 4th ed, text rev. Washington, D.C: American Psychiatric Association; 2000.
12. Robinson RG, Parikh RM, Lipsey JR, et al. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 1993;150:286-93.
13. Schiffer RB, Herndon RM, Rudick RA. Treatment of pathologic laughing and weeping with amitriptyline. N Engl J Med 1985;312(23):1480-2.
14. Anderson G, Vestergaard K, Riis JO. Citalopram for post-stroke pathological crying. Lancet 1993;342(8875):837-9.
15. Müller U, Murai T, Bauer-Wittmund T, von Cramon DY. Paroxetine versus citalopram treatment of pathological crying after brain injury. Brain Inj 1999;13(10):805-11.
16. Burns A, Russell E, Stratton-Powell H, et al. Sertraline in stroke-associated lability of mood. Int J Geriatr Psychiatry 1999;14(8):681-5.
17. Kim SW, Shin IS, Kim JM, et al. Mirtazapine treatment for pathological laughing and crying after stroke. Clin Neuropharmacol 2005;28:249-51.
18. Udaka F, Yamao S, Nagata H, et al. Pathologic laughing and crying treated with levodopa. Arch Neurol 1984;41:1095-6.
19. Brooks BR, Thisted RA, Appel SH, et al. Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology 2004;63:1364-70.
20. Panitch HS, Thisted RA, Smith RA, et al. Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis. Ann Neurol 2006;59:780-7.
21. Werling LL, Keller A, Frank JG, Nuwayhid SJ. A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder. Exp Neurol 2007;207(2):248-57.
22. Starkstein SE, Migliorelli R, Teson A, et al. Prevalence and clinical correlates of pathological affective display in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1995;59:55-60.
23. Tateno A, Jorge RE, Robinson RG. Pathological laughing and crying following traumatic brain injury. J Neuropsychiatry Clin Neurosci 2004;16:426-34.
24. Moore SR, Gresham LS, Bromberg MB, et al. A self report measure of affective lability. J Neurol Neurosurg Psychiatry 1997;63:89-93.
25. Smith RA, Berg JE, Pope LE, et al. Validation of the CNS emotional lability scale for pseudobulbar affect (pathological laughing and crying) in multiple sclerosis patients. Mult Scler 2004;10:679-85.
Mrs. R, a 68-year-old retired teacher, is referred to you for suspected mania after a closed head injury from a car accident. The referring physician reports that Mrs. R experienced mild anterograde amnesia that has resolved, but she continues to suffer from “persistent mood swings as evidenced by substantial inappropriate laughter.”
Mrs. R is not manic. Her mood is normal, with a relatively euthymic affect. When asked about her accident or injury, however, she breaks into bouts of laughter that appear to be uncontrollable and last up to several minutes. These episodes include respiratory changes that make her laughter nearly indistinguishable from crying. Mrs. R explains that the episodes occur every time she discusses the accident—regardless of her efforts to prevent them—and complains they are extremely frustrating and embarrassing. She avoids situations that might trigger the episodes.
Patients with involuntary emotional expression disorder (IEED)—a neurologic disorder that manifests as brief bouts of uncontrollable crying, laughing, or both—may appear to have bipolar disorder, schizophrenia, depression, or another psychiatric disorder. Careful evaluation, however, can distinguish IEED from other conditions. Managing the disorder requires an understanding of IEED phenomenology, including:
- neurologic conditions that result in IEED
- underlying pathology
- diagnostic criteria
- effective treatments.
Brain dysfunction alters affect
IEED was introduced as an inclusive term, replacing previous nomenclature such as pathologic laughing and crying, pseudobulbar affect, affective lability, and emotional incontinence.1
IEED can present as episodes of laughter, as in Mrs. R’s case, but more commonly manifests as bouts of crying. Other presentations include a combination of laughing and crying, but episodic outbursts of other emotions that are out of the patient’s control—such as anger—can be included in this syndrome.2 IEED episodes can lead to embarrassment, frustration, and anger that eventually can affect mood and often cause patients to avoid social interaction.3
IEED can occur in any condition that damages and affects the brain areas critical to emotional motor output (Box 1).4-6 The broad pattern of lesions that can result in IEED stems from many disease states. IEED is often observed in amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, and traumatic brain injury. It also may occur in dementia, Parkinson’s disease, and other disorders (Table 1).7
Table 1
Neurologic conditions associated with IEED
| Amyotrophic lateral sclerosis |
| Multiple sclerosis |
| Traumatic brain injury |
| Stroke |
| Alzheimer’s disease |
| Frontotemporal dementia |
| Parkinson’s disease |
| Progressive supranuclear palsy |
| Multiple systems atrophy |
| Wilson’s disease |
| Normal pressure hydrocephalus |
| Olivopontine cerebellar atrophy |
| Source: Reference 7 |
Diagnosis can be elusive
Although IEED is not included in DSM-IV-TR, recently developed diagnostic criteria can help distinguish it from other disorders (Table 2).1 As with DSM-categorized disorders, IEED must result in clinically significant distress or impairment in social or occupational function and must not be better accounted for by another disorder or caused by a physiologic substance.
The patient must present with symptoms caused by brain dysfunction from brain injury or neurodegenerative disease. Underlying brain damage might not be apparent when the patient first presents, but to our knowledge no case of idiopathic IEED has been described. If a patient presents with symptoms thought to be IEED, first determine what underlying neurologic condition is causing the symptoms and optimally manage this disorder.
Symptoms must be incongruent with or in excess of the person’s underlying mood and independent or in excess of the provoking stimulus. Inappropriateness of the emotional response is the hallmark of IEED.
Some characteristics support—but are not essential for—an IEED diagnosis:
- autonomic symptoms, such as flushing of the face and increased salivary production during episodes
- pseudobulbar signs, such as increased jaw jerk, exaggerated gag reflex, dysarthria, and dysphagia
- other emotional outbursts.
Table 2
Is it IEED? Diagnostic criteria
| Presence of brain damage |
Episodes of involuntary emotional motor output that:
|
Disorder is not:
|
| Source: Reference 1 |
Characteristics of IEED episodes
| Paroxysmal, sudden onset with rapid offset |
| Brief (up to several minutes) |
| Stereotyped across patients (may manifest in similar fashion from patient to patient) |
| Stereotyped within patients (episodes often have similar type, severity, and eliciting stimuli) |
Damage to the descending inputs to the pontomedullary area once referred to as the faciorespiratory center is most likely to result in release of bulbar function and, subsequently, involuntary emotional expression disorder (IEED). Therefore, because of the progressive upper motor neuron degeneration associated with amyotrophic lateral sclerosis (ALS), nearly 50% of ALS patients will eventually demonstrate pathological affect.4
The lesions that can result in IEED are diffuse, however, and have been described in a review of IEED neuroanatomy as including a cortico-limbic-subcortico-thalamo-ponto-cerebellar network.5 Single lesions to white matter structures—such as the internal capsule—and gray matter structures—such as the thalamus, hypothalamus, basal ganglia, cerebellum, and several cortical locations—have been associated with IEED. Bilateral lesions are more likely to produce the disorder than single lesions.
With such varied neuroanatomic substrates, predicting the underlying neurochemical pathology of IEED is difficult. Among the neurotransmitters considered in IEED pathology and treatment are serotonin, glutamate, and dopamine. The sigma-1 receptor system may also play a role.6
CASE CONTINUED: Reaching a diagnosis
After thoroughly interviewing Mrs. R, you exclude mood disorders such as depression or bipolar disorder. The paroxysmal, episodic nature of her emotional outbursts and the consistency of the eliciting stimulus, suggest IEED.
Distinguishing IEED from depression. Physicians may be quick to diagnose a patient with consistent, recurrent crying as having a depressive disorder. In IEED, the patient’s family commonly (and inappropriately) will confirm this misperception, even if the patient claims otherwise. The hallmark distinctions between depression and IEED are:
- duration of crying
- associated mood state.
Patients who suffer from MDD, however, are not excluded from an IEED diagnosis. In 1 small study, almost one-half of patients with IEED also had major depression.12 Differentiating these syndromes—even in patients who suffer from both—is important to ensure proper management and patient and family understanding of the condition. Lastly, although IEED is not a mood disorder, the embarrassment and frustration it causes can change a patient’s mood over time.
Recommended treatment
Education. In our experience, education is critical to help patients and family members understand IEED and deal with embarrassment and other normal reactions they may experience. Explain that these emotional displays are not manic or psychotic episodes but periods of motor dyscontrol caused by a neurologic condition.
Teach them to cope with IEED by:
- identifying and avoiding stimuli that provoke IEED episodes
- ignoring the episodes and continuing with usual activities.
These agents have IEED-specific therapeutic effects through a mechanism independent of their antidepressant action. In patients with IEED and depression, antidepressants may resolve IEED while depression remains refractory.2,12 Potential drawbacks include anticholinergic effects with TCAs and sexual and gastrointestinal side effects with SSRIs. Nevertheless, these agents are the optimal first-line therapy for IEED among currently available options.
Other agents. Small studies have investigated other agents, but the data are insufficient to warrant recommendations for clinical practice. One study found that the novel antidepressant mirtazapine improved symptoms in 2 patients who did not respond to SSRIs.17 In another study, levodopa therapy resulted in improvement in 10 of 25 patients.18
Among scales that measure involuntary emotional expression disorder (IEED) severity, 2 have been used in studies of IEED therapeutic efficacy (see Related Resources):12,19,20
- Pathological Laughing and Crying Scale (PLACS) developed by Robinson et al12 is an interviewer-administered, 18-item tool that has been validated in IEED patients with stroke,12 dementia,22and traumatic brain injury.23
- 7-item Center for Neurologic Study-Lability Scale (CNS-LS) is a self-report measure that has been validated in IEED patients with amyotrophic lateral sclerosis24 and multiple sclerosis.25
Although these scales have been used primarily for research, you can use them clinically to establish a baseline of IEED severity and gauge treatment efficacy. Improved scores generally correlate with successful treatment; if a patient fails to show adequate response on 1 of these scales, consider changing treatment.
A combination dextromethorphan and quinidine (DM/Q) is being evaluated for IEED. This compound has demonstrated efficacy in IEED patients with ALS19 and MS20 and is in Phase III clinical development. DM/Q is thought to be a potent activator of the sigma-1 receptor system as well as an N-methyl-D-aspartate antagonist.21
Table 4
IEED: Evidence for antidepressants
| Drug | Study design/population | Dosage | Outcome |
|---|---|---|---|
| Tricyclics | |||
| Amitriptyline | Schiffer et al;13 double-blind crossover; 12 multiple sclerosis patients | Mean: 57.8 mg/d | 8 patients showed significant improvement compared with placebo |
| Nortriptyline | Robinson et al;12 double-blind, placebo-controlled; 28 stroke patients | ≤100 mg/d | Patients receiving nortriptyline reported significantly greater improvement on PLACS at 4 and 6 weeks compared with placebo |
| Selective serotonin reuptake inhibitors | |||
| Citalopram | Anderson et al;14 double-blind, placebo-controlled crossover; 16 stroke patients | 10 to 20 mg/d | Citalopram decreased the number of daily crying episodes by ≥50% compared with placebo |
| Fluoxetine | Choi-Kwon et al;2 double-blind placebo-controlled; 152 patients | 20 mg/d | Fluoxetine significantly improved measures of IEED and anger proneness but not depression |
| Paroxetine | Müller et al;15 consecutive case series, comparison with citalopram; 26 patients with traumatic brain injury or stroke | 10 to 40 mg/d | Both paroxetine and citalopram resulted in significant improvements in measures of emotionalism |
| Sertraline | Burns et al;16 double-blind, placebo-controlled; 28 stroke patients | 50 mg/d | Patients receiving sertraline had significant improvements in measures of emotionalism |
| IEED: involuntary emotional expression disorder; PLACS: Pathological Laughing and Crying Scale | |||
CASE CONTINUED: Effective pharmacotherapy
After diagnosing IEED, you start Mrs. R on sertraline, 50 mg/d. She experiences a nearly immediate reduction in the number of daily IEED episodes. As a result, she feels more comfortable engaging in social activities.
Effective pharmacologic intervention can greatly improve patients’ quality of life.19,20 Use scales that measure IEED severity to gauge treatment effectiveness (Box 2).12,19,20,22-25 Because treatment failure is a realistic possibility,17 you may need to try a variety of agents to determine which regimen provides the greatest efficacy and therapeutic effects.
- Involuntary emotional expressive disorder (for healthcare professionals). www.ieed.org/hp.
- Pathological laughing and crying scale (PLACS). Robinson RG, Parikh RM, Lipsey JR, et al. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 1993;150:286-93.
- Center for neurologic study—lability scale (CNS-LS). Moore SR, Gresham LS, Bromberg MB, et al. A self report measure of affective lability. J Neurol Neurosurg Psychiatry 1997;63:89-93.
- Amitriptyline • Elavil, Endep
- Citalopram • Celexa
- Dextromethorphan/quinidine • Zenvia*
- Fluoxetine • Prozac
- Levodopa • Larodopa
- Mirtazapine • Remeron
- Nortriptyline • Aventyl
- Paroxetine • Paxil
- Sertraline • Zoloft
- * IN PHASE III DEVELOPMENT
Dr. Grill reports no financial relationship with any company whose products are mentioned in the article or with manufacturers of competing products.
Dr. Cummings is a consultant to Acadia Pharmaceuticals, Astellas Pharma, Avanir Pharmaceuticals, Cephalon, CoMentis, Eisai, Eli Lilly and Company, EnVivo Pharmaceuticals, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merck, Merz Pharma, Myriad, Neurochem, Novartis, Ono Pharmaceutical Co., Pfizer Inc., and sanofi-aventis. He is a speaker for Eisai, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merz Pharma, Novartis, and Pfizer Inc.
Mrs. R, a 68-year-old retired teacher, is referred to you for suspected mania after a closed head injury from a car accident. The referring physician reports that Mrs. R experienced mild anterograde amnesia that has resolved, but she continues to suffer from “persistent mood swings as evidenced by substantial inappropriate laughter.”
Mrs. R is not manic. Her mood is normal, with a relatively euthymic affect. When asked about her accident or injury, however, she breaks into bouts of laughter that appear to be uncontrollable and last up to several minutes. These episodes include respiratory changes that make her laughter nearly indistinguishable from crying. Mrs. R explains that the episodes occur every time she discusses the accident—regardless of her efforts to prevent them—and complains they are extremely frustrating and embarrassing. She avoids situations that might trigger the episodes.
Patients with involuntary emotional expression disorder (IEED)—a neurologic disorder that manifests as brief bouts of uncontrollable crying, laughing, or both—may appear to have bipolar disorder, schizophrenia, depression, or another psychiatric disorder. Careful evaluation, however, can distinguish IEED from other conditions. Managing the disorder requires an understanding of IEED phenomenology, including:
- neurologic conditions that result in IEED
- underlying pathology
- diagnostic criteria
- effective treatments.
Brain dysfunction alters affect
IEED was introduced as an inclusive term, replacing previous nomenclature such as pathologic laughing and crying, pseudobulbar affect, affective lability, and emotional incontinence.1
IEED can present as episodes of laughter, as in Mrs. R’s case, but more commonly manifests as bouts of crying. Other presentations include a combination of laughing and crying, but episodic outbursts of other emotions that are out of the patient’s control—such as anger—can be included in this syndrome.2 IEED episodes can lead to embarrassment, frustration, and anger that eventually can affect mood and often cause patients to avoid social interaction.3
IEED can occur in any condition that damages and affects the brain areas critical to emotional motor output (Box 1).4-6 The broad pattern of lesions that can result in IEED stems from many disease states. IEED is often observed in amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, and traumatic brain injury. It also may occur in dementia, Parkinson’s disease, and other disorders (Table 1).7
Table 1
Neurologic conditions associated with IEED
| Amyotrophic lateral sclerosis |
| Multiple sclerosis |
| Traumatic brain injury |
| Stroke |
| Alzheimer’s disease |
| Frontotemporal dementia |
| Parkinson’s disease |
| Progressive supranuclear palsy |
| Multiple systems atrophy |
| Wilson’s disease |
| Normal pressure hydrocephalus |
| Olivopontine cerebellar atrophy |
| Source: Reference 7 |
Diagnosis can be elusive
Although IEED is not included in DSM-IV-TR, recently developed diagnostic criteria can help distinguish it from other disorders (Table 2).1 As with DSM-categorized disorders, IEED must result in clinically significant distress or impairment in social or occupational function and must not be better accounted for by another disorder or caused by a physiologic substance.
The patient must present with symptoms caused by brain dysfunction from brain injury or neurodegenerative disease. Underlying brain damage might not be apparent when the patient first presents, but to our knowledge no case of idiopathic IEED has been described. If a patient presents with symptoms thought to be IEED, first determine what underlying neurologic condition is causing the symptoms and optimally manage this disorder.
Symptoms must be incongruent with or in excess of the person’s underlying mood and independent or in excess of the provoking stimulus. Inappropriateness of the emotional response is the hallmark of IEED.
Some characteristics support—but are not essential for—an IEED diagnosis:
- autonomic symptoms, such as flushing of the face and increased salivary production during episodes
- pseudobulbar signs, such as increased jaw jerk, exaggerated gag reflex, dysarthria, and dysphagia
- other emotional outbursts.
Table 2
Is it IEED? Diagnostic criteria
| Presence of brain damage |
Episodes of involuntary emotional motor output that:
|
Disorder is not:
|
| Source: Reference 1 |
Characteristics of IEED episodes
| Paroxysmal, sudden onset with rapid offset |
| Brief (up to several minutes) |
| Stereotyped across patients (may manifest in similar fashion from patient to patient) |
| Stereotyped within patients (episodes often have similar type, severity, and eliciting stimuli) |
Damage to the descending inputs to the pontomedullary area once referred to as the faciorespiratory center is most likely to result in release of bulbar function and, subsequently, involuntary emotional expression disorder (IEED). Therefore, because of the progressive upper motor neuron degeneration associated with amyotrophic lateral sclerosis (ALS), nearly 50% of ALS patients will eventually demonstrate pathological affect.4
The lesions that can result in IEED are diffuse, however, and have been described in a review of IEED neuroanatomy as including a cortico-limbic-subcortico-thalamo-ponto-cerebellar network.5 Single lesions to white matter structures—such as the internal capsule—and gray matter structures—such as the thalamus, hypothalamus, basal ganglia, cerebellum, and several cortical locations—have been associated with IEED. Bilateral lesions are more likely to produce the disorder than single lesions.
With such varied neuroanatomic substrates, predicting the underlying neurochemical pathology of IEED is difficult. Among the neurotransmitters considered in IEED pathology and treatment are serotonin, glutamate, and dopamine. The sigma-1 receptor system may also play a role.6
CASE CONTINUED: Reaching a diagnosis
After thoroughly interviewing Mrs. R, you exclude mood disorders such as depression or bipolar disorder. The paroxysmal, episodic nature of her emotional outbursts and the consistency of the eliciting stimulus, suggest IEED.
Distinguishing IEED from depression. Physicians may be quick to diagnose a patient with consistent, recurrent crying as having a depressive disorder. In IEED, the patient’s family commonly (and inappropriately) will confirm this misperception, even if the patient claims otherwise. The hallmark distinctions between depression and IEED are:
- duration of crying
- associated mood state.
Patients who suffer from MDD, however, are not excluded from an IEED diagnosis. In 1 small study, almost one-half of patients with IEED also had major depression.12 Differentiating these syndromes—even in patients who suffer from both—is important to ensure proper management and patient and family understanding of the condition. Lastly, although IEED is not a mood disorder, the embarrassment and frustration it causes can change a patient’s mood over time.
Recommended treatment
Education. In our experience, education is critical to help patients and family members understand IEED and deal with embarrassment and other normal reactions they may experience. Explain that these emotional displays are not manic or psychotic episodes but periods of motor dyscontrol caused by a neurologic condition.
Teach them to cope with IEED by:
- identifying and avoiding stimuli that provoke IEED episodes
- ignoring the episodes and continuing with usual activities.
These agents have IEED-specific therapeutic effects through a mechanism independent of their antidepressant action. In patients with IEED and depression, antidepressants may resolve IEED while depression remains refractory.2,12 Potential drawbacks include anticholinergic effects with TCAs and sexual and gastrointestinal side effects with SSRIs. Nevertheless, these agents are the optimal first-line therapy for IEED among currently available options.
Other agents. Small studies have investigated other agents, but the data are insufficient to warrant recommendations for clinical practice. One study found that the novel antidepressant mirtazapine improved symptoms in 2 patients who did not respond to SSRIs.17 In another study, levodopa therapy resulted in improvement in 10 of 25 patients.18
Among scales that measure involuntary emotional expression disorder (IEED) severity, 2 have been used in studies of IEED therapeutic efficacy (see Related Resources):12,19,20
- Pathological Laughing and Crying Scale (PLACS) developed by Robinson et al12 is an interviewer-administered, 18-item tool that has been validated in IEED patients with stroke,12 dementia,22and traumatic brain injury.23
- 7-item Center for Neurologic Study-Lability Scale (CNS-LS) is a self-report measure that has been validated in IEED patients with amyotrophic lateral sclerosis24 and multiple sclerosis.25
Although these scales have been used primarily for research, you can use them clinically to establish a baseline of IEED severity and gauge treatment efficacy. Improved scores generally correlate with successful treatment; if a patient fails to show adequate response on 1 of these scales, consider changing treatment.
A combination dextromethorphan and quinidine (DM/Q) is being evaluated for IEED. This compound has demonstrated efficacy in IEED patients with ALS19 and MS20 and is in Phase III clinical development. DM/Q is thought to be a potent activator of the sigma-1 receptor system as well as an N-methyl-D-aspartate antagonist.21
Table 4
IEED: Evidence for antidepressants
| Drug | Study design/population | Dosage | Outcome |
|---|---|---|---|
| Tricyclics | |||
| Amitriptyline | Schiffer et al;13 double-blind crossover; 12 multiple sclerosis patients | Mean: 57.8 mg/d | 8 patients showed significant improvement compared with placebo |
| Nortriptyline | Robinson et al;12 double-blind, placebo-controlled; 28 stroke patients | ≤100 mg/d | Patients receiving nortriptyline reported significantly greater improvement on PLACS at 4 and 6 weeks compared with placebo |
| Selective serotonin reuptake inhibitors | |||
| Citalopram | Anderson et al;14 double-blind, placebo-controlled crossover; 16 stroke patients | 10 to 20 mg/d | Citalopram decreased the number of daily crying episodes by ≥50% compared with placebo |
| Fluoxetine | Choi-Kwon et al;2 double-blind placebo-controlled; 152 patients | 20 mg/d | Fluoxetine significantly improved measures of IEED and anger proneness but not depression |
| Paroxetine | Müller et al;15 consecutive case series, comparison with citalopram; 26 patients with traumatic brain injury or stroke | 10 to 40 mg/d | Both paroxetine and citalopram resulted in significant improvements in measures of emotionalism |
| Sertraline | Burns et al;16 double-blind, placebo-controlled; 28 stroke patients | 50 mg/d | Patients receiving sertraline had significant improvements in measures of emotionalism |
| IEED: involuntary emotional expression disorder; PLACS: Pathological Laughing and Crying Scale | |||
CASE CONTINUED: Effective pharmacotherapy
After diagnosing IEED, you start Mrs. R on sertraline, 50 mg/d. She experiences a nearly immediate reduction in the number of daily IEED episodes. As a result, she feels more comfortable engaging in social activities.
Effective pharmacologic intervention can greatly improve patients’ quality of life.19,20 Use scales that measure IEED severity to gauge treatment effectiveness (Box 2).12,19,20,22-25 Because treatment failure is a realistic possibility,17 you may need to try a variety of agents to determine which regimen provides the greatest efficacy and therapeutic effects.
- Involuntary emotional expressive disorder (for healthcare professionals). www.ieed.org/hp.
- Pathological laughing and crying scale (PLACS). Robinson RG, Parikh RM, Lipsey JR, et al. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 1993;150:286-93.
- Center for neurologic study—lability scale (CNS-LS). Moore SR, Gresham LS, Bromberg MB, et al. A self report measure of affective lability. J Neurol Neurosurg Psychiatry 1997;63:89-93.
- Amitriptyline • Elavil, Endep
- Citalopram • Celexa
- Dextromethorphan/quinidine • Zenvia*
- Fluoxetine • Prozac
- Levodopa • Larodopa
- Mirtazapine • Remeron
- Nortriptyline • Aventyl
- Paroxetine • Paxil
- Sertraline • Zoloft
- * IN PHASE III DEVELOPMENT
Dr. Grill reports no financial relationship with any company whose products are mentioned in the article or with manufacturers of competing products.
Dr. Cummings is a consultant to Acadia Pharmaceuticals, Astellas Pharma, Avanir Pharmaceuticals, Cephalon, CoMentis, Eisai, Eli Lilly and Company, EnVivo Pharmaceuticals, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merck, Merz Pharma, Myriad, Neurochem, Novartis, Ono Pharmaceutical Co., Pfizer Inc., and sanofi-aventis. He is a speaker for Eisai, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merz Pharma, Novartis, and Pfizer Inc.
1. Cummings JL, Arciniegas DB, Brooks BR, et al. Defining and diagnosing involuntary emotional expression disorder. CNS Spectr 2006;11:1-7.
2. Choi-Kwon S, Han SW, Kwon SU, et al. Fluoxetine treatment in poststroke depression, emotional incontinence, and anger proneness: a double-blind, placebo-controlled study. Stroke 2006;37:156-61.
3. Lieberman A, Benson DF. Control of emotional expression in pseudobulbar palsy. A personal experience. Arch Neurol 1977;34:717-9.
4. Caroscio JT, Mulvihill MN, Sterling R, Abrams B. Amyotrophic lateral sclerosis. Its natural history. Neurol Clin 1987;5:1-8.
5. Arciniegas DB, Lauterbach EC, Anderson KE, et al. The differential diagnosis of pseudobulbar affect (PBA). Distinguishing PBA among disorders of mood and affect. Proceedings of a roundtable meeting. CNS Spectr 2005;10:1-14; quiz 15-16.-
6. Rabins PV, Arciniegas DB. Pathophysiology of involuntary emotional expression disorder. CNS Spectr 2007;12:17-22.
7. Arciniegas DB, Topkoff J. The neuropsychiatry of pathologic affect: an approach to evaluation and treatment. Semin Clin Neuropsychiatry 2000;5:290-306.
8. Green RL, McAllister TW, Bernat JL. A study of crying in medically and surgically hospitalized patients. Am J Psychiatry 1987;144:442-7.
9. Dark FL, McGrath JJ, Ron MA. Pathological laughing and crying. Aust N Z J Psychiatry 1996;30:472-9.
10. Wilson S. Some problems in neurology. II. Pathological laughing and crying. J Neurol Psychopathol 1924;16:299-333.
11. Diagnostic and statistical manual of mental disorders. 4th ed, text rev. Washington, D.C: American Psychiatric Association; 2000.
12. Robinson RG, Parikh RM, Lipsey JR, et al. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 1993;150:286-93.
13. Schiffer RB, Herndon RM, Rudick RA. Treatment of pathologic laughing and weeping with amitriptyline. N Engl J Med 1985;312(23):1480-2.
14. Anderson G, Vestergaard K, Riis JO. Citalopram for post-stroke pathological crying. Lancet 1993;342(8875):837-9.
15. Müller U, Murai T, Bauer-Wittmund T, von Cramon DY. Paroxetine versus citalopram treatment of pathological crying after brain injury. Brain Inj 1999;13(10):805-11.
16. Burns A, Russell E, Stratton-Powell H, et al. Sertraline in stroke-associated lability of mood. Int J Geriatr Psychiatry 1999;14(8):681-5.
17. Kim SW, Shin IS, Kim JM, et al. Mirtazapine treatment for pathological laughing and crying after stroke. Clin Neuropharmacol 2005;28:249-51.
18. Udaka F, Yamao S, Nagata H, et al. Pathologic laughing and crying treated with levodopa. Arch Neurol 1984;41:1095-6.
19. Brooks BR, Thisted RA, Appel SH, et al. Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology 2004;63:1364-70.
20. Panitch HS, Thisted RA, Smith RA, et al. Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis. Ann Neurol 2006;59:780-7.
21. Werling LL, Keller A, Frank JG, Nuwayhid SJ. A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder. Exp Neurol 2007;207(2):248-57.
22. Starkstein SE, Migliorelli R, Teson A, et al. Prevalence and clinical correlates of pathological affective display in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1995;59:55-60.
23. Tateno A, Jorge RE, Robinson RG. Pathological laughing and crying following traumatic brain injury. J Neuropsychiatry Clin Neurosci 2004;16:426-34.
24. Moore SR, Gresham LS, Bromberg MB, et al. A self report measure of affective lability. J Neurol Neurosurg Psychiatry 1997;63:89-93.
25. Smith RA, Berg JE, Pope LE, et al. Validation of the CNS emotional lability scale for pseudobulbar affect (pathological laughing and crying) in multiple sclerosis patients. Mult Scler 2004;10:679-85.
1. Cummings JL, Arciniegas DB, Brooks BR, et al. Defining and diagnosing involuntary emotional expression disorder. CNS Spectr 2006;11:1-7.
2. Choi-Kwon S, Han SW, Kwon SU, et al. Fluoxetine treatment in poststroke depression, emotional incontinence, and anger proneness: a double-blind, placebo-controlled study. Stroke 2006;37:156-61.
3. Lieberman A, Benson DF. Control of emotional expression in pseudobulbar palsy. A personal experience. Arch Neurol 1977;34:717-9.
4. Caroscio JT, Mulvihill MN, Sterling R, Abrams B. Amyotrophic lateral sclerosis. Its natural history. Neurol Clin 1987;5:1-8.
5. Arciniegas DB, Lauterbach EC, Anderson KE, et al. The differential diagnosis of pseudobulbar affect (PBA). Distinguishing PBA among disorders of mood and affect. Proceedings of a roundtable meeting. CNS Spectr 2005;10:1-14; quiz 15-16.-
6. Rabins PV, Arciniegas DB. Pathophysiology of involuntary emotional expression disorder. CNS Spectr 2007;12:17-22.
7. Arciniegas DB, Topkoff J. The neuropsychiatry of pathologic affect: an approach to evaluation and treatment. Semin Clin Neuropsychiatry 2000;5:290-306.
8. Green RL, McAllister TW, Bernat JL. A study of crying in medically and surgically hospitalized patients. Am J Psychiatry 1987;144:442-7.
9. Dark FL, McGrath JJ, Ron MA. Pathological laughing and crying. Aust N Z J Psychiatry 1996;30:472-9.
10. Wilson S. Some problems in neurology. II. Pathological laughing and crying. J Neurol Psychopathol 1924;16:299-333.
11. Diagnostic and statistical manual of mental disorders. 4th ed, text rev. Washington, D.C: American Psychiatric Association; 2000.
12. Robinson RG, Parikh RM, Lipsey JR, et al. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 1993;150:286-93.
13. Schiffer RB, Herndon RM, Rudick RA. Treatment of pathologic laughing and weeping with amitriptyline. N Engl J Med 1985;312(23):1480-2.
14. Anderson G, Vestergaard K, Riis JO. Citalopram for post-stroke pathological crying. Lancet 1993;342(8875):837-9.
15. Müller U, Murai T, Bauer-Wittmund T, von Cramon DY. Paroxetine versus citalopram treatment of pathological crying after brain injury. Brain Inj 1999;13(10):805-11.
16. Burns A, Russell E, Stratton-Powell H, et al. Sertraline in stroke-associated lability of mood. Int J Geriatr Psychiatry 1999;14(8):681-5.
17. Kim SW, Shin IS, Kim JM, et al. Mirtazapine treatment for pathological laughing and crying after stroke. Clin Neuropharmacol 2005;28:249-51.
18. Udaka F, Yamao S, Nagata H, et al. Pathologic laughing and crying treated with levodopa. Arch Neurol 1984;41:1095-6.
19. Brooks BR, Thisted RA, Appel SH, et al. Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology 2004;63:1364-70.
20. Panitch HS, Thisted RA, Smith RA, et al. Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis. Ann Neurol 2006;59:780-7.
21. Werling LL, Keller A, Frank JG, Nuwayhid SJ. A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder. Exp Neurol 2007;207(2):248-57.
22. Starkstein SE, Migliorelli R, Teson A, et al. Prevalence and clinical correlates of pathological affective display in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1995;59:55-60.
23. Tateno A, Jorge RE, Robinson RG. Pathological laughing and crying following traumatic brain injury. J Neuropsychiatry Clin Neurosci 2004;16:426-34.
24. Moore SR, Gresham LS, Bromberg MB, et al. A self report measure of affective lability. J Neurol Neurosurg Psychiatry 1997;63:89-93.
25. Smith RA, Berg JE, Pope LE, et al. Validation of the CNS emotional lability scale for pseudobulbar affect (pathological laughing and crying) in multiple sclerosis patients. Mult Scler 2004;10:679-85.
Memantine: New option for advanced Alzheimer’s
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
| Drug brand name: Namenda |
| Class: NMDA receptor antagonist |
| FDA-approved indication: Moderate to severe Alzheimer’s disease |
| Approval date: Oct. 17, 2003 |
| Manufacturer: Forest Pharmaceuticals |
| Dosing forms: 5 mg, 10 mg (“titration packets” containing 5-mg and 10-mg tablets are available) |
| Recommended dosage: Begin at 5 mg/d for 1 week; increase to 5 mg bid the second week, then to 10 mg in the morning and 5 mg in the evening for the third week; increase to 10 mg bid for continued dosing |
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.
:
1. Holt WF. Glutamate in health and disease: the role of inhibitors. In: Bar PR, Beal MF (eds). Neuroprotection in CNS diseases. New York: Marcel Dekker, 1997;87-119.
2. Parsons CG, Danysz W, Quack G. Memantine and the aminoalkyl-cyclohexane MRZ 2/579 are moderate affinity uncompetitive NMDA receptor antagonists—in vitro characterisation. Amino Acids 2000;19:157-66.
3. Parsons CG, Danysz W, Quack G. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacol 1999;38:735-67.
4. Merz Pharma. Scientific information: Akatinol memantine Frankfurt, Germany: Merz Pharma clinical research department, 1998:44.
5. Axura (memantine) product information. Available at: http://www.pharmaworld.com
6. Kilpatrick GJ, Tilbrook GS. Memantine. Merz. Curr Opin Investig Drugs 2002;3:798-806.
7. Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 1999;14:135-46.
8. Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003;348:1333-41.
9. Tariot P, Farlow M, Grossberg G, et al. Memantine/donepezil dualtherapy is superior to placebo/donepezil therapy for treatment of moderate to severe Alzheimer’s disease. San Juan, Puerto Rico: American College of Neuropsychopharmacology annual meeting, 2002.
10. Ambrozi L, Danielczyk W. Treatment of impaired cerebral function in psychogeriatric patients with memantine—results of a phase II double-blind study. Pharmacopsychiatry 1988;21:144-6.
11. Gortelmeyer R, Erbler H. Memantine in the treatment of mild to moderate dementia syndrome. A double-blind placebo-controlled study. Arzneimittelforschung 1992;42:904-13.
12. Fleischhacker WW, Buchgeher A, Schubert H. Memantine in the treatment of senile dementia of the Alzheimer type. Prog Neuropsychopharmacol Biol Psychiatry 1986;10:87-93.
13. Hartmann S, Mobius HJ. Tolerability of memantine in combination with cholinesterase inhibitors in dementia therapy. Int Clin Psychopharmacol 2003;18:81-5.
14. Wenk GL, Quack G, Mobius HJ, Danysz W. No interaction of memantine with acetylcholinesterase inhibitors approved for clinical use. Life Sciences 2000;66:1079-83.
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
| Drug brand name: Namenda |
| Class: NMDA receptor antagonist |
| FDA-approved indication: Moderate to severe Alzheimer’s disease |
| Approval date: Oct. 17, 2003 |
| Manufacturer: Forest Pharmaceuticals |
| Dosing forms: 5 mg, 10 mg (“titration packets” containing 5-mg and 10-mg tablets are available) |
| Recommended dosage: Begin at 5 mg/d for 1 week; increase to 5 mg bid the second week, then to 10 mg in the morning and 5 mg in the evening for the third week; increase to 10 mg bid for continued dosing |
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
| Drug brand name: Namenda |
| Class: NMDA receptor antagonist |
| FDA-approved indication: Moderate to severe Alzheimer’s disease |
| Approval date: Oct. 17, 2003 |
| Manufacturer: Forest Pharmaceuticals |
| Dosing forms: 5 mg, 10 mg (“titration packets” containing 5-mg and 10-mg tablets are available) |
| Recommended dosage: Begin at 5 mg/d for 1 week; increase to 5 mg bid the second week, then to 10 mg in the morning and 5 mg in the evening for the third week; increase to 10 mg bid for continued dosing |
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.
:
1. Holt WF. Glutamate in health and disease: the role of inhibitors. In: Bar PR, Beal MF (eds). Neuroprotection in CNS diseases. New York: Marcel Dekker, 1997;87-119.
2. Parsons CG, Danysz W, Quack G. Memantine and the aminoalkyl-cyclohexane MRZ 2/579 are moderate affinity uncompetitive NMDA receptor antagonists—in vitro characterisation. Amino Acids 2000;19:157-66.
3. Parsons CG, Danysz W, Quack G. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacol 1999;38:735-67.
4. Merz Pharma. Scientific information: Akatinol memantine Frankfurt, Germany: Merz Pharma clinical research department, 1998:44.
5. Axura (memantine) product information. Available at: http://www.pharmaworld.com
6. Kilpatrick GJ, Tilbrook GS. Memantine. Merz. Curr Opin Investig Drugs 2002;3:798-806.
7. Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 1999;14:135-46.
8. Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003;348:1333-41.
9. Tariot P, Farlow M, Grossberg G, et al. Memantine/donepezil dualtherapy is superior to placebo/donepezil therapy for treatment of moderate to severe Alzheimer’s disease. San Juan, Puerto Rico: American College of Neuropsychopharmacology annual meeting, 2002.
10. Ambrozi L, Danielczyk W. Treatment of impaired cerebral function in psychogeriatric patients with memantine—results of a phase II double-blind study. Pharmacopsychiatry 1988;21:144-6.
11. Gortelmeyer R, Erbler H. Memantine in the treatment of mild to moderate dementia syndrome. A double-blind placebo-controlled study. Arzneimittelforschung 1992;42:904-13.
12. Fleischhacker WW, Buchgeher A, Schubert H. Memantine in the treatment of senile dementia of the Alzheimer type. Prog Neuropsychopharmacol Biol Psychiatry 1986;10:87-93.
13. Hartmann S, Mobius HJ. Tolerability of memantine in combination with cholinesterase inhibitors in dementia therapy. Int Clin Psychopharmacol 2003;18:81-5.
14. Wenk GL, Quack G, Mobius HJ, Danysz W. No interaction of memantine with acetylcholinesterase inhibitors approved for clinical use. Life Sciences 2000;66:1079-83.
:
1. Holt WF. Glutamate in health and disease: the role of inhibitors. In: Bar PR, Beal MF (eds). Neuroprotection in CNS diseases. New York: Marcel Dekker, 1997;87-119.
2. Parsons CG, Danysz W, Quack G. Memantine and the aminoalkyl-cyclohexane MRZ 2/579 are moderate affinity uncompetitive NMDA receptor antagonists—in vitro characterisation. Amino Acids 2000;19:157-66.
3. Parsons CG, Danysz W, Quack G. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacol 1999;38:735-67.
4. Merz Pharma. Scientific information: Akatinol memantine Frankfurt, Germany: Merz Pharma clinical research department, 1998:44.
5. Axura (memantine) product information. Available at: http://www.pharmaworld.com
6. Kilpatrick GJ, Tilbrook GS. Memantine. Merz. Curr Opin Investig Drugs 2002;3:798-806.
7. Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 1999;14:135-46.
8. Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003;348:1333-41.
9. Tariot P, Farlow M, Grossberg G, et al. Memantine/donepezil dualtherapy is superior to placebo/donepezil therapy for treatment of moderate to severe Alzheimer’s disease. San Juan, Puerto Rico: American College of Neuropsychopharmacology annual meeting, 2002.
10. Ambrozi L, Danielczyk W. Treatment of impaired cerebral function in psychogeriatric patients with memantine—results of a phase II double-blind study. Pharmacopsychiatry 1988;21:144-6.
11. Gortelmeyer R, Erbler H. Memantine in the treatment of mild to moderate dementia syndrome. A double-blind placebo-controlled study. Arzneimittelforschung 1992;42:904-13.
12. Fleischhacker WW, Buchgeher A, Schubert H. Memantine in the treatment of senile dementia of the Alzheimer type. Prog Neuropsychopharmacol Biol Psychiatry 1986;10:87-93.
13. Hartmann S, Mobius HJ. Tolerability of memantine in combination with cholinesterase inhibitors in dementia therapy. Int Clin Psychopharmacol 2003;18:81-5.
14. Wenk GL, Quack G, Mobius HJ, Danysz W. No interaction of memantine with acetylcholinesterase inhibitors approved for clinical use. Life Sciences 2000;66:1079-83.