Harold W. Goforth, MD

Presenting symptoms: Marital memories

Ms. A, age 83, has been experiencing increasing confusion, agitation, and memory loss across 4 to 5 years. Family members say her memory loss has become prominent within the last year. She can no longer cook, manage her finances, shop, or perform other basic activities. At times she does not recognize her husband of 62 years and needs help with bathing and grooming.

Ms. A’s Folstein Mini-Mental State Examination (MMSE) score is 18, indicating moderate dementia. She exhibits disorientation, diminished short-term memory, impaired attention including apraxia, and executive dysfunction. Her Geriatric Depression Scale (15-item short form) score indicates normal mood.

A neurologic exam reveals mild parkinsonism, including mild bilateral upper-extremity cogwheeltype rigidity and questionable frontal release signs including a possible mild bilateral grasp reflex. No snout reflex was seen.

This presentation suggests Ms. A has:

• Alzheimer’s disease
• Lewy body dementia
• or vascular dementia

The authors’ observations:

Differentiating among Alzheimer’s, Lewy body, and vascular dementias is important (Table 1), as their treatments and clinical courses differ.

The initial workup’s goal is to diagnose a reversible medical condition that may be hastening cognitive decline. Brain imaging (CT or MRI) can uncover cerebrovascular disease, subdural hematomas, normal-pressure hydrocephalus, tumors, or other cerebral diseases. Laboratory tests can reveal systemic conditions such as hypothyroidism, vitamin B12 deficiency, hypercalcemia, neurosyphilis, or HIV infection.¹

Table 1

Differences in Alzheimer’s, Lewy body, and vascular dementias

With a thorough history and laboratory testing, a diagnosis of “probable” AD can be as much as 85% accurate. Probable AD is characterized by progressive gradual decline of cognitive functions affecting memory and at least one other domain including executive dysfunction, apraxia, aphasia, and/or agnosia. These deficits must cause significant functional impairment.

Neurologic test results may support AD diagnosis after ruling out reversible causes of dementia. Neuropsychological testing can provide valuable early information when subtle findings cannot be ascertained on clinical screening. (For a listing of neuropsychological tests, see this article at currentpsychiatry.com.)

Diagnosis: An unpredictable patient

Ms. A received a CBC; comprehensive metabolic panel; urinalysis; screens for rapid plasma reagin, B12, folate, and homocysteine levels; and a brain MRI. Hemoglobin and serum albumin were mildly depressed, reflecting early malnutrition. MRI showed generalized cerebral atrophy. Significant vascular disease was not identified.

Ms. A was diagnosed as having probable Alzheimer’s-type dementia based on the test results and the fact that her cognition was steadily declining. Other explanatory mechanisms were absent. She did not exhibit hallucinatory psychosis or fluctuating consciousness, which would signal Lewy body dementia.

Table 2

Medications for treating agitation in Alzheimer’s dementia

The psychiatrist started galantamine, 4 mg bid, and vitamin E, 400 IU bid, to maximize her cognition and attempt to slow her functional decline. Ms. A, who was in an assisted living facility when we evaluated her, was transferred to the facility’s nursing section shortly afterward.

At follow-up 3 weeks later, Ms. A’s behavior improved moderately, but she remained unpredictable and intermittently agitated. Staff reported that she was physically assaulting caregivers two to three times weekly.

Which medication(s) would you use to control Ms. A’s agitation and paranoia?

• an SSRI
• a mood stabilizer
• an atypical antipsychotic
• a combination or two or more of these drug classes

The authors’ observations

Aside from controlling agitation, medication treatment in AD should slow cognitive decline, improve behavior, help the patient perform daily activities, and delay nursing home placement.

• Watch for drug-drug interactions. Many patients with AD also are taking medications for hypertension, hypercholesterolemia, diabetes, arthritis, and other medical comorbidities.
• Start low and go slow. Older patients generally do not tolerate rapid dos-ing adjustments as well as younger patients (Table 2).

SSRIS. Selective serotonin reuptake inhibitors increase serotonin at the synaptic terminal. Serotonin has long been associated with impulsivity and aggression, and decreased 5-hydroxyindole acetic acid, a metabolite of serotonin, has been found in violent criminals and in psychiatric patients who have demonstrated inward or outward aggression.¹¹

SSRIs generally are tolerable, safe, effective, and have little cholinergic blockade. Citalopram and sertraline minimally inhibit the cytochrome P-450 2D6 isoenzyme and have lower proteinbinding affinities than fluoxetine or paroxetine. Thus, citalopram and sertraline are less likely to alter therapeutic levels of highly bound medications through displacement of either drug’s protein-bound portion.¹⁰

Anticonvulsants with mood-stabilizing effects are another option. Reasonably strong data support use of divalproex for managing agitation in AD, either as a first-line agent or as an adjunct after failed SSRI therapy. Unlike other anticonvulsants, divalproex also may be neuroprotective.³

Divalproex, however, is associated with white blood cell suppression, significant liver toxicity, and pancreatitis, although these effects are rare.¹³ Monitor white blood cell counts and liver enzymes early in treatment, even if divalproex blood levels below the standard reference range produce a response.¹⁴

Though not studied specifically for treating agitation in AD, carbamazepine has demonstrated significant short-term efficacy in treating dementia-related agitation and aggression.² Scant data support use of gabapentin or lamotrigine in Alzheimer’s dementia, but these agents are often used to manage agitation in other disorders.

Atypical antipsychotics. Psychosis usually occurs in middle-to-late-stage AD but can occur at any point. If psychosis occurs early, rule out Lewy body dementia.¹⁵

Choose an atypical antipsychotic that exhibits rapid dopamine receptor dissociation constants to reduce the risk of extrapyramidal symptoms, tardive dyskinesia, and cognitive decline with prolonged use. Quetiapine has shown efficacy for treating behavioral problems in Alzheimer’s and Lewy body dementia,⁷ and its sedating effects may help regulate sleep-wake cycles.

Data support use of olanzapine for agitation in AD,⁶ but watch for anticholinergic effects including worsening of cognition. Fast-dissolving olanzapine and risperidone oral wafers may help circumvent dosing difficulties in patients who cannot swallow—or will not take—their medication. Intramuscular olanzapine and ziprasidone have shown efficacy in treating acute agitation, but no systematic studies have examined their use in agitation secondary to dementia.

Recent data suggest a modestly increased risk of cerebrovascular accidents in AD patients taking atypicals compared with placebo, but the absolute rate of such events remains low.

Treatment: 3 months of stability

Ms. A’s galantamine dosage was increased to 8 mg bid and sertraline—25 mg/d for 7 days, then 50 mg/d—was added in an effort to better control her agitation, but the behavior continued unabated for 2 weeks. Divalproex, 125 mg bid titrated over 4 weeks to 750 mg/d, was added. Still, her agitation persisted.

Over the next 4 to 6 weeks, Ms. A showed signs of psychosis, often talking to herself and occasionally reporting “people attacking me.” She became paranoid toward members of her church, who she said were “trying to hurt” her. The paranoia intensified her agitation and disrupted her sleep. Physical examination was unremarkable, as were chest X-ray and urinalysis.

Sertraline and divalproex were gradually discontinued. Quetiapine—25 mg nightly, titrated across 2 weeks to 150 mg nightly—was started. Ms. A’s agitation and psychosis decreased with quetiapine titration, and her sleep improved. Her paranoid delusions remained but no longer impeded functioning or prompted a violent reaction.

Then after remaining stable for about 3 months, Ms. A’s paranoid delusions worsened and her agitation increased.

What treatment options are available at this point?

The authors’ observations

Treating agitation and delaying nursing home placement for patients with AD is challenging. When faced with inadequate or no response, consider less-conventional alternatives.

Vitamin E and selegiline were found separately to postpone functional decline in ambulatory patients with moderately severe AD, but the agents given together were less effective than either agent alone.¹⁶

Use of methylphenidate,¹⁷ buspirone,¹⁸ clonazepam,¹⁹ zolpidem,²⁰ and—most recently— memantine²¹ for AD-related agitation also has been described.

Continued treatment: Medication changes

Quetiapine was increased to 350 mg nightly across 4 weeks, resulting in mild to moderate improvement. The higher dosage did not significantly worsen rigidity or motor function, and Ms. A tolerated the increased dosage without clinical orthostasis.

Memantine was added to address Ms. A’s agitation and preserve function. The agent was started at 5 mg/d and titrated across 4 weeks to 10 mg bid.

On clinical exam, Ms. A was more calm and directable and required less intervention. Her paranoia also decreased, allowing improved interaction with family, caregivers, and others. Ms. A remains stable on memantine, 10 mg bid; galantamine, 8 mg; quetiapine, 350 mg nightly; and vitamin E, 400 IU bid. Her cognitive ability has gradually declined over the past 18 months, as evidenced by her most recent MMSE score of 16/30.

Related resources

• Cummings JL. Use of cholinesterase inhibitors in clinical practice: evidence-based recommendations. Am J Geriatr Psychiatry 2003; 11:131-45.
• Alzheimer’s Disease Education and Referral Center, a service of the National Institute on Aging. http://www.alzheimers.org.
• Paleacu D, Mazeh D, Mirecki I, et al. Donepezil for the treatment of behavioral symptoms in patients with Alzheimer’s disease. Clin Neuropharmacol 2002;25:313-7.
• Tariot PN, Loy R, Ryan JM, et al. Mood stabilizers in Alzheimer’s disease: symptomatic and neuroprotective rationales. Adv Drug Deliv Rev 2002;54:1567-77.

Drug brand names

• Buspirone • BuSpar
• Carbamazepine • Tegretol
• Citalopram • Celexa
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Divalproex • Depakote, DepakoteER
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Galantamine • Reminyl
• Lamotrigine • Lamictal
• Memantine • Namenda
• Methylphenidate • Concerta, Ritalin
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone wafers • RisperdalM-Tabs
• Rivastigmine • Exelon
• Selegiline • Eldepryl
• Sertraline • Zoloft
• Ziprasidone • Geodon
• Zolpidem • Ambien

Disclosure

Dr. Goforth is a speaker for Pfizer Inc., Forest Pharmaceuticals, and BristolMyers Squibb Co., and has received grant support from Pfizer Inc. He has also received support from the Bristol-Myers Squibb Fellowship in Geriatric Psychiatry through the American Association of Geriatric Psychiatry.

Dr. Rao is a speaker for Pfizer Inc.

Drs. Raval and Ruth report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Presenting symptoms: Marital memories

Ms. A, age 83, has been experiencing increasing confusion, agitation, and memory loss across 4 to 5 years. Family members say her memory loss has become prominent within the last year. She can no longer cook, manage her finances, shop, or perform other basic activities. At times she does not recognize her husband of 62 years and needs help with bathing and grooming.

Ms. A’s Folstein Mini-Mental State Examination (MMSE) score is 18, indicating moderate dementia. She exhibits disorientation, diminished short-term memory, impaired attention including apraxia, and executive dysfunction. Her Geriatric Depression Scale (15-item short form) score indicates normal mood.

A neurologic exam reveals mild parkinsonism, including mild bilateral upper-extremity cogwheeltype rigidity and questionable frontal release signs including a possible mild bilateral grasp reflex. No snout reflex was seen.

This presentation suggests Ms. A has:

• Alzheimer’s disease
• Lewy body dementia
• or vascular dementia

The authors’ observations:

Differentiating among Alzheimer’s, Lewy body, and vascular dementias is important (Table 1), as their treatments and clinical courses differ.

The initial workup’s goal is to diagnose a reversible medical condition that may be hastening cognitive decline. Brain imaging (CT or MRI) can uncover cerebrovascular disease, subdural hematomas, normal-pressure hydrocephalus, tumors, or other cerebral diseases. Laboratory tests can reveal systemic conditions such as hypothyroidism, vitamin B12 deficiency, hypercalcemia, neurosyphilis, or HIV infection.¹

Table 1

Differences in Alzheimer’s, Lewy body, and vascular dementias

With a thorough history and laboratory testing, a diagnosis of “probable” AD can be as much as 85% accurate. Probable AD is characterized by progressive gradual decline of cognitive functions affecting memory and at least one other domain including executive dysfunction, apraxia, aphasia, and/or agnosia. These deficits must cause significant functional impairment.

Neurologic test results may support AD diagnosis after ruling out reversible causes of dementia. Neuropsychological testing can provide valuable early information when subtle findings cannot be ascertained on clinical screening. (For a listing of neuropsychological tests, see this article at currentpsychiatry.com.)

Diagnosis: An unpredictable patient

Ms. A received a CBC; comprehensive metabolic panel; urinalysis; screens for rapid plasma reagin, B12, folate, and homocysteine levels; and a brain MRI. Hemoglobin and serum albumin were mildly depressed, reflecting early malnutrition. MRI showed generalized cerebral atrophy. Significant vascular disease was not identified.

Ms. A was diagnosed as having probable Alzheimer’s-type dementia based on the test results and the fact that her cognition was steadily declining. Other explanatory mechanisms were absent. She did not exhibit hallucinatory psychosis or fluctuating consciousness, which would signal Lewy body dementia.

Table 2

Medications for treating agitation in Alzheimer’s dementia

The psychiatrist started galantamine, 4 mg bid, and vitamin E, 400 IU bid, to maximize her cognition and attempt to slow her functional decline. Ms. A, who was in an assisted living facility when we evaluated her, was transferred to the facility’s nursing section shortly afterward.

At follow-up 3 weeks later, Ms. A’s behavior improved moderately, but she remained unpredictable and intermittently agitated. Staff reported that she was physically assaulting caregivers two to three times weekly.

Which medication(s) would you use to control Ms. A’s agitation and paranoia?

• an SSRI
• a mood stabilizer
• an atypical antipsychotic
• a combination or two or more of these drug classes

The authors’ observations

Aside from controlling agitation, medication treatment in AD should slow cognitive decline, improve behavior, help the patient perform daily activities, and delay nursing home placement.

• Watch for drug-drug interactions. Many patients with AD also are taking medications for hypertension, hypercholesterolemia, diabetes, arthritis, and other medical comorbidities.
• Start low and go slow. Older patients generally do not tolerate rapid dos-ing adjustments as well as younger patients (Table 2).

SSRIS. Selective serotonin reuptake inhibitors increase serotonin at the synaptic terminal. Serotonin has long been associated with impulsivity and aggression, and decreased 5-hydroxyindole acetic acid, a metabolite of serotonin, has been found in violent criminals and in psychiatric patients who have demonstrated inward or outward aggression.¹¹

SSRIs generally are tolerable, safe, effective, and have little cholinergic blockade. Citalopram and sertraline minimally inhibit the cytochrome P-450 2D6 isoenzyme and have lower proteinbinding affinities than fluoxetine or paroxetine. Thus, citalopram and sertraline are less likely to alter therapeutic levels of highly bound medications through displacement of either drug’s protein-bound portion.¹⁰

Anticonvulsants with mood-stabilizing effects are another option. Reasonably strong data support use of divalproex for managing agitation in AD, either as a first-line agent or as an adjunct after failed SSRI therapy. Unlike other anticonvulsants, divalproex also may be neuroprotective.³

Divalproex, however, is associated with white blood cell suppression, significant liver toxicity, and pancreatitis, although these effects are rare.¹³ Monitor white blood cell counts and liver enzymes early in treatment, even if divalproex blood levels below the standard reference range produce a response.¹⁴

Though not studied specifically for treating agitation in AD, carbamazepine has demonstrated significant short-term efficacy in treating dementia-related agitation and aggression.² Scant data support use of gabapentin or lamotrigine in Alzheimer’s dementia, but these agents are often used to manage agitation in other disorders.

Atypical antipsychotics. Psychosis usually occurs in middle-to-late-stage AD but can occur at any point. If psychosis occurs early, rule out Lewy body dementia.¹⁵

Choose an atypical antipsychotic that exhibits rapid dopamine receptor dissociation constants to reduce the risk of extrapyramidal symptoms, tardive dyskinesia, and cognitive decline with prolonged use. Quetiapine has shown efficacy for treating behavioral problems in Alzheimer’s and Lewy body dementia,⁷ and its sedating effects may help regulate sleep-wake cycles.

Data support use of olanzapine for agitation in AD,⁶ but watch for anticholinergic effects including worsening of cognition. Fast-dissolving olanzapine and risperidone oral wafers may help circumvent dosing difficulties in patients who cannot swallow—or will not take—their medication. Intramuscular olanzapine and ziprasidone have shown efficacy in treating acute agitation, but no systematic studies have examined their use in agitation secondary to dementia.

Recent data suggest a modestly increased risk of cerebrovascular accidents in AD patients taking atypicals compared with placebo, but the absolute rate of such events remains low.

Treatment: 3 months of stability

Ms. A’s galantamine dosage was increased to 8 mg bid and sertraline—25 mg/d for 7 days, then 50 mg/d—was added in an effort to better control her agitation, but the behavior continued unabated for 2 weeks. Divalproex, 125 mg bid titrated over 4 weeks to 750 mg/d, was added. Still, her agitation persisted.

Over the next 4 to 6 weeks, Ms. A showed signs of psychosis, often talking to herself and occasionally reporting “people attacking me.” She became paranoid toward members of her church, who she said were “trying to hurt” her. The paranoia intensified her agitation and disrupted her sleep. Physical examination was unremarkable, as were chest X-ray and urinalysis.

Sertraline and divalproex were gradually discontinued. Quetiapine—25 mg nightly, titrated across 2 weeks to 150 mg nightly—was started. Ms. A’s agitation and psychosis decreased with quetiapine titration, and her sleep improved. Her paranoid delusions remained but no longer impeded functioning or prompted a violent reaction.

Then after remaining stable for about 3 months, Ms. A’s paranoid delusions worsened and her agitation increased.

What treatment options are available at this point?

The authors’ observations

Treating agitation and delaying nursing home placement for patients with AD is challenging. When faced with inadequate or no response, consider less-conventional alternatives.

Vitamin E and selegiline were found separately to postpone functional decline in ambulatory patients with moderately severe AD, but the agents given together were less effective than either agent alone.¹⁶

Use of methylphenidate,¹⁷ buspirone,¹⁸ clonazepam,¹⁹ zolpidem,²⁰ and—most recently— memantine²¹ for AD-related agitation also has been described.

Continued treatment: Medication changes

Quetiapine was increased to 350 mg nightly across 4 weeks, resulting in mild to moderate improvement. The higher dosage did not significantly worsen rigidity or motor function, and Ms. A tolerated the increased dosage without clinical orthostasis.

Memantine was added to address Ms. A’s agitation and preserve function. The agent was started at 5 mg/d and titrated across 4 weeks to 10 mg bid.

On clinical exam, Ms. A was more calm and directable and required less intervention. Her paranoia also decreased, allowing improved interaction with family, caregivers, and others. Ms. A remains stable on memantine, 10 mg bid; galantamine, 8 mg; quetiapine, 350 mg nightly; and vitamin E, 400 IU bid. Her cognitive ability has gradually declined over the past 18 months, as evidenced by her most recent MMSE score of 16/30.

Related resources

• Cummings JL. Use of cholinesterase inhibitors in clinical practice: evidence-based recommendations. Am J Geriatr Psychiatry 2003; 11:131-45.
• Alzheimer’s Disease Education and Referral Center, a service of the National Institute on Aging. http://www.alzheimers.org.
• Paleacu D, Mazeh D, Mirecki I, et al. Donepezil for the treatment of behavioral symptoms in patients with Alzheimer’s disease. Clin Neuropharmacol 2002;25:313-7.
• Tariot PN, Loy R, Ryan JM, et al. Mood stabilizers in Alzheimer’s disease: symptomatic and neuroprotective rationales. Adv Drug Deliv Rev 2002;54:1567-77.

Drug brand names

• Buspirone • BuSpar
• Carbamazepine • Tegretol
• Citalopram • Celexa
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Divalproex • Depakote, DepakoteER
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Galantamine • Reminyl
• Lamotrigine • Lamictal
• Memantine • Namenda
• Methylphenidate • Concerta, Ritalin
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone wafers • RisperdalM-Tabs
• Rivastigmine • Exelon
• Selegiline • Eldepryl
• Sertraline • Zoloft
• Ziprasidone • Geodon
• Zolpidem • Ambien

Disclosure

Dr. Goforth is a speaker for Pfizer Inc., Forest Pharmaceuticals, and BristolMyers Squibb Co., and has received grant support from Pfizer Inc. He has also received support from the Bristol-Myers Squibb Fellowship in Geriatric Psychiatry through the American Association of Geriatric Psychiatry.

Dr. Rao is a speaker for Pfizer Inc.

Drs. Raval and Ruth report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Presenting symptoms: Marital memories

Ms. A, age 83, has been experiencing increasing confusion, agitation, and memory loss across 4 to 5 years. Family members say her memory loss has become prominent within the last year. She can no longer cook, manage her finances, shop, or perform other basic activities. At times she does not recognize her husband of 62 years and needs help with bathing and grooming.

Ms. A’s Folstein Mini-Mental State Examination (MMSE) score is 18, indicating moderate dementia. She exhibits disorientation, diminished short-term memory, impaired attention including apraxia, and executive dysfunction. Her Geriatric Depression Scale (15-item short form) score indicates normal mood.

A neurologic exam reveals mild parkinsonism, including mild bilateral upper-extremity cogwheeltype rigidity and questionable frontal release signs including a possible mild bilateral grasp reflex. No snout reflex was seen.

This presentation suggests Ms. A has:

• Alzheimer’s disease
• Lewy body dementia
• or vascular dementia

The authors’ observations:

Differentiating among Alzheimer’s, Lewy body, and vascular dementias is important (Table 1), as their treatments and clinical courses differ.

The initial workup’s goal is to diagnose a reversible medical condition that may be hastening cognitive decline. Brain imaging (CT or MRI) can uncover cerebrovascular disease, subdural hematomas, normal-pressure hydrocephalus, tumors, or other cerebral diseases. Laboratory tests can reveal systemic conditions such as hypothyroidism, vitamin B12 deficiency, hypercalcemia, neurosyphilis, or HIV infection.¹

Table 1

Differences in Alzheimer’s, Lewy body, and vascular dementias

With a thorough history and laboratory testing, a diagnosis of “probable” AD can be as much as 85% accurate. Probable AD is characterized by progressive gradual decline of cognitive functions affecting memory and at least one other domain including executive dysfunction, apraxia, aphasia, and/or agnosia. These deficits must cause significant functional impairment.

Neurologic test results may support AD diagnosis after ruling out reversible causes of dementia. Neuropsychological testing can provide valuable early information when subtle findings cannot be ascertained on clinical screening. (For a listing of neuropsychological tests, see this article at currentpsychiatry.com.)

Diagnosis: An unpredictable patient

Ms. A received a CBC; comprehensive metabolic panel; urinalysis; screens for rapid plasma reagin, B12, folate, and homocysteine levels; and a brain MRI. Hemoglobin and serum albumin were mildly depressed, reflecting early malnutrition. MRI showed generalized cerebral atrophy. Significant vascular disease was not identified.

Ms. A was diagnosed as having probable Alzheimer’s-type dementia based on the test results and the fact that her cognition was steadily declining. Other explanatory mechanisms were absent. She did not exhibit hallucinatory psychosis or fluctuating consciousness, which would signal Lewy body dementia.

Table 2

Medications for treating agitation in Alzheimer’s dementia

The psychiatrist started galantamine, 4 mg bid, and vitamin E, 400 IU bid, to maximize her cognition and attempt to slow her functional decline. Ms. A, who was in an assisted living facility when we evaluated her, was transferred to the facility’s nursing section shortly afterward.

At follow-up 3 weeks later, Ms. A’s behavior improved moderately, but she remained unpredictable and intermittently agitated. Staff reported that she was physically assaulting caregivers two to three times weekly.

Which medication(s) would you use to control Ms. A’s agitation and paranoia?

• an SSRI
• a mood stabilizer
• an atypical antipsychotic
• a combination or two or more of these drug classes

The authors’ observations

Aside from controlling agitation, medication treatment in AD should slow cognitive decline, improve behavior, help the patient perform daily activities, and delay nursing home placement.

• Watch for drug-drug interactions. Many patients with AD also are taking medications for hypertension, hypercholesterolemia, diabetes, arthritis, and other medical comorbidities.
• Start low and go slow. Older patients generally do not tolerate rapid dos-ing adjustments as well as younger patients (Table 2).

SSRIS. Selective serotonin reuptake inhibitors increase serotonin at the synaptic terminal. Serotonin has long been associated with impulsivity and aggression, and decreased 5-hydroxyindole acetic acid, a metabolite of serotonin, has been found in violent criminals and in psychiatric patients who have demonstrated inward or outward aggression.¹¹

SSRIs generally are tolerable, safe, effective, and have little cholinergic blockade. Citalopram and sertraline minimally inhibit the cytochrome P-450 2D6 isoenzyme and have lower proteinbinding affinities than fluoxetine or paroxetine. Thus, citalopram and sertraline are less likely to alter therapeutic levels of highly bound medications through displacement of either drug’s protein-bound portion.¹⁰

Anticonvulsants with mood-stabilizing effects are another option. Reasonably strong data support use of divalproex for managing agitation in AD, either as a first-line agent or as an adjunct after failed SSRI therapy. Unlike other anticonvulsants, divalproex also may be neuroprotective.³

Divalproex, however, is associated with white blood cell suppression, significant liver toxicity, and pancreatitis, although these effects are rare.¹³ Monitor white blood cell counts and liver enzymes early in treatment, even if divalproex blood levels below the standard reference range produce a response.¹⁴

Though not studied specifically for treating agitation in AD, carbamazepine has demonstrated significant short-term efficacy in treating dementia-related agitation and aggression.² Scant data support use of gabapentin or lamotrigine in Alzheimer’s dementia, but these agents are often used to manage agitation in other disorders.

Atypical antipsychotics. Psychosis usually occurs in middle-to-late-stage AD but can occur at any point. If psychosis occurs early, rule out Lewy body dementia.¹⁵

Choose an atypical antipsychotic that exhibits rapid dopamine receptor dissociation constants to reduce the risk of extrapyramidal symptoms, tardive dyskinesia, and cognitive decline with prolonged use. Quetiapine has shown efficacy for treating behavioral problems in Alzheimer’s and Lewy body dementia,⁷ and its sedating effects may help regulate sleep-wake cycles.

Data support use of olanzapine for agitation in AD,⁶ but watch for anticholinergic effects including worsening of cognition. Fast-dissolving olanzapine and risperidone oral wafers may help circumvent dosing difficulties in patients who cannot swallow—or will not take—their medication. Intramuscular olanzapine and ziprasidone have shown efficacy in treating acute agitation, but no systematic studies have examined their use in agitation secondary to dementia.

Recent data suggest a modestly increased risk of cerebrovascular accidents in AD patients taking atypicals compared with placebo, but the absolute rate of such events remains low.

Treatment: 3 months of stability

Ms. A’s galantamine dosage was increased to 8 mg bid and sertraline—25 mg/d for 7 days, then 50 mg/d—was added in an effort to better control her agitation, but the behavior continued unabated for 2 weeks. Divalproex, 125 mg bid titrated over 4 weeks to 750 mg/d, was added. Still, her agitation persisted.

Over the next 4 to 6 weeks, Ms. A showed signs of psychosis, often talking to herself and occasionally reporting “people attacking me.” She became paranoid toward members of her church, who she said were “trying to hurt” her. The paranoia intensified her agitation and disrupted her sleep. Physical examination was unremarkable, as were chest X-ray and urinalysis.

Sertraline and divalproex were gradually discontinued. Quetiapine—25 mg nightly, titrated across 2 weeks to 150 mg nightly—was started. Ms. A’s agitation and psychosis decreased with quetiapine titration, and her sleep improved. Her paranoid delusions remained but no longer impeded functioning or prompted a violent reaction.

Then after remaining stable for about 3 months, Ms. A’s paranoid delusions worsened and her agitation increased.

What treatment options are available at this point?

The authors’ observations

Treating agitation and delaying nursing home placement for patients with AD is challenging. When faced with inadequate or no response, consider less-conventional alternatives.

Vitamin E and selegiline were found separately to postpone functional decline in ambulatory patients with moderately severe AD, but the agents given together were less effective than either agent alone.¹⁶

Use of methylphenidate,¹⁷ buspirone,¹⁸ clonazepam,¹⁹ zolpidem,²⁰ and—most recently— memantine²¹ for AD-related agitation also has been described.

Continued treatment: Medication changes

Quetiapine was increased to 350 mg nightly across 4 weeks, resulting in mild to moderate improvement. The higher dosage did not significantly worsen rigidity or motor function, and Ms. A tolerated the increased dosage without clinical orthostasis.

Memantine was added to address Ms. A’s agitation and preserve function. The agent was started at 5 mg/d and titrated across 4 weeks to 10 mg bid.

On clinical exam, Ms. A was more calm and directable and required less intervention. Her paranoia also decreased, allowing improved interaction with family, caregivers, and others. Ms. A remains stable on memantine, 10 mg bid; galantamine, 8 mg; quetiapine, 350 mg nightly; and vitamin E, 400 IU bid. Her cognitive ability has gradually declined over the past 18 months, as evidenced by her most recent MMSE score of 16/30.

Related resources

• Cummings JL. Use of cholinesterase inhibitors in clinical practice: evidence-based recommendations. Am J Geriatr Psychiatry 2003; 11:131-45.
• Alzheimer’s Disease Education and Referral Center, a service of the National Institute on Aging. http://www.alzheimers.org.
• Paleacu D, Mazeh D, Mirecki I, et al. Donepezil for the treatment of behavioral symptoms in patients with Alzheimer’s disease. Clin Neuropharmacol 2002;25:313-7.
• Tariot PN, Loy R, Ryan JM, et al. Mood stabilizers in Alzheimer’s disease: symptomatic and neuroprotective rationales. Adv Drug Deliv Rev 2002;54:1567-77.

Drug brand names

• Buspirone • BuSpar
• Carbamazepine • Tegretol
• Citalopram • Celexa
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Divalproex • Depakote, DepakoteER
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Galantamine • Reminyl
• Lamotrigine • Lamictal
• Memantine • Namenda
• Methylphenidate • Concerta, Ritalin
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone wafers • RisperdalM-Tabs
• Rivastigmine • Exelon
• Selegiline • Eldepryl
• Sertraline • Zoloft
• Ziprasidone • Geodon
• Zolpidem • Ambien

Disclosure

Dr. Goforth is a speaker for Pfizer Inc., Forest Pharmaceuticals, and BristolMyers Squibb Co., and has received grant support from Pfizer Inc. He has also received support from the Bristol-Myers Squibb Fellowship in Geriatric Psychiatry through the American Association of Geriatric Psychiatry.

Dr. Rao is a speaker for Pfizer Inc.

Drs. Raval and Ruth report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.