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Preventing late-life suicide: 6 steps to detect the warning signs
CASE REPORT: I have a gun
Mr. V, age 77, appears depressed and anxious during his appointment at a mental hygiene clinic. He reports insomnia, concentration trouble, and anhedonia. He tells the psychiatrist he keeps a loaded gun at home and is not sure he can control his suicidal impulses.
The patient is Caucasian and has a history of heart failure, pulmonary disease, and type 2 diabetes. His wife died 18 months ago. He lives alone, but his sister lives nearby. He recently received a right hip replacement, which required 3 months of rehabilitation in a nursing home to recover from surgical complications. He still has trouble walking.
As in Mr. V’s case, treating older patients referred for psychiatric care often involves evaluating suicide risk. His age, race, gender, depressed mood, recent bereavement, and medical ailments place him in the population at highest risk of suicide (Box, Table 1).1-8
Approximately 20% of all suicides in the United States are committed by persons age 65 or older,1 who account for 13% of the total population. The suicide rate among persons older than 75 is three times higher than it is for the young.2 Older Caucasian men have the highest per-capita rate of completed suicide, compared with any other group of Americans.3
Psychiatric disorders. The rates of Axis I disorders among older persons who commit suicide fall within the average range for all age groups (70 to 90%). However, the types of disorders seen in the older population differ from those of younger suicides (Table 1).4-8
Affective illness has been termed “the predominant psychopathology associated with suicide in later life.”4 Among older persons who commit suicide, three-fourths (76%) have diagnosable mood disorders4 and nearly two-thirds (63%) have depression.6 Contributing risk factors include alcoholism and substance abuse,4,6,7 Axis II disorders, and dementia.6
Losses and medical illness. In later life, bereavement, loss of independence, or financial reversals may lead to depression. Older persons who take their own lives also tend to have greater physical health burdens and more functional disabilities than those who do not commit suicide.6,8
This article describes an age-based psychiatric workup of the suicidal older patient, including factors to consider when screening for depressive symptoms, prescribing drug therapy, and determining the need for hospitalization.
AGE-BASED CLINICAL WORKUP
For older patients who report suicidal ideation, an age-appropriate workup—using clinical interviews and screening instruments—is essential. The clinical interview can build rapport and gather information about the patient’s suicidal plan or intent. Based on our experience, we recommend the following 6-step screening interview, summarized in Table 2.
- Ask about a specific plan. Does the patient have the means readily available to carry out this plan? What is the timeline (imminent versus vaguely futuristic)? Does the patient report having control over this plan?
- Gather a suicide history. Has the patient attempted suicide before? By what means? Is there a family history of suicide? If yes, by what means did this family member commit suicide, and how was the patient affected?
- Assess social status. How isolated is the patient? Have there been recent changes in his or her social circle, such as loss of a spouse? Can the patient identify at least one person who would be negatively affected by the suicide?
- Assess medical health. Does the patient suffer from chronic pain? Does the patient have a recently diagnosed medical condition? Has a longstanding medical condition become more debilitating? Does the patient report feeling hopeless about impending medical difficulties? Has he or she been keeping regularly scheduled medical appointments with outpatient clinicians?
- Assess mental health. Does the patient meet DSM-IV criteria for depression or schizophrenia, which are associated with high suicide risk? Does he or she report being hopeless or helpless? Is the suicidal ideation ego dystonic?
- Ascertain clinical signs of suicidal intent. Has the patient:
Table 1
Suicide risk with mental and physical illness, by patient age
| Risk factors | Young (21 to 34 yrs) | Middle-aged (35 to 54 yrs) | Young-old (55 to 74 yrs) | Elderly (77+ yrs) |
|---|---|---|---|---|
| Psychiatric disorders | • | • | • | • |
| Mood disorders | ○ | • | • | |
| Alcohol abuse | ○ | • | ○ | |
| Primary psychoses | • | ○ | ||
| Personality disorders | ○ | |||
| Physical ailments | • | • | ||
| • Significant risk factor ○ Potential risk factor | ||||
| Source: Compiled from information in references 4-8. | ||||
CASE REPORT continued: Some telling signs
Mr. V’s laboratory screening reveals slightly elevated serum glucose and mild anemia. An ECG reveals a type I heart block, but all other lab results are unremarkable. His sister reports he recently gave away his dog, which he and his wife had owned for many years. He has also mentioned a desire to revise his will when speaking to other family members. Hospital records indicate he has missed numerous medical appointments over the past 4 months.
SCREENING INSTRUMENTS
Psychological assessments can often buttress the clinical interview findings. Several measurements are well-suited for detecting suicidal risk and concomitant depression (Table 3).
Beck SSI-C. The Beck Scale for Suicide Ideation – Current (SSI-C) assesses a patient’s preparation and motivation to commit suicide.9 This short (19-item) self-report measure asks patients to rate their wish to die, desire to attempt suicide, duration (and frequency) of suicidal thoughts, sense of control over suicide, and deterrents they face. The SSI-C helps to measure or monitor suicidality and is reliable and valid for psychiatric outpatients.9
BDI-II. The Beck Depression Inventory—recently revised in a second edition (BDI-II)10—can be useful because depression is one of the strongest risk factors for elder suicide. The 21-item BDI-II—a psychometrically sound, self-report instrument—asks about general symptoms of depression and gauges their severity. It can be applied to diverse patient populations and ages11 and is appropriate for older patients who are also being treated medically.
Beck Hopelessness Scale. Hopelessness has been recognized as a possible harbinger of suicide.12 One study showed that depression became a clinically meaningful suicide predictor only when accompanied by hopelessness.13
A score of 10 or more on the Beck Hopelessness Scale identified 91% of patients in one study who eventually committed suicide. The hopelessness patients expressed on this scale more strongly differentiated between those who did or did not commit suicide than did their scores on the BDI or SSI-C.14
Table 2
6-step clinical interview with an older suicidal patient
|
|
| Source: Adapted from the Cincinnati Veterans Affairs Medical Center general psychological suicide assessment |
HRSD-R. The revised Hamilton Rating Scale for Depression (HRSD-R) documents patients’ levels of mood disturbance and suicidality. One item in this 21-item, clinician-administered instrument specifically asks about the patient’s level of suicidality in the past week. The scale has well-documented reliability and validity and is appropriate for psychiatric populations.15
CASE REPORT continued: Alarming findings
Along with the clinical interview, Mr. V. is screened with the Beck Hopelessness Scale and Beck Depression Inventory-II. These instruments are chosen because they are easy to administer, and patients can readily comprehend the questions—even when under duress. Mr. V’s results reveal moderate depression and severe hopelessness.
INPATIENT VS. OUTPATIENT CARE
Older patients are often referred to a psychiatrist because of vague suicidal ideation, but they may also present in an acute crisis—with immediate plans for suicide and readily accessible means. The first concern for their safety is to ensure they are not left alone.
Patient interview. First, listen empathetically and ask detailed questions, especially ones that remind patients of their daily connections and responsibilities. For instance, ask, “Do you have children who would be affected by your decision?” Address patients’ immediate needs, such as hunger, thirst, or pain.16 Work on building a therapeutic alliance before asking questions that may appear trivial to agitated patients (such as tasks assessing cognitive abilities).
Avoid arguing with patients, and refrain from offering advice or sermonizing. Allow them to describe their emotions, and communicate that you understand their concerns. Discuss how they can expect to receive treatment to ease their discomfort. Inform them that mental health specialists can treat them and monitor their progress.
Hospitalization. Begin discussing treatment options and broach the notion of hospital admission if necessary. One way to foster an alliance is to frame inpatient care as a way of helping them recover from their crisis in a safe environment.
To ensure patient safety, it is best to err on the side of admission. Admitting the suicidal patient not only guarantees strict supervision but also allows time for necessary psychological assessment. Hospitalization may also allow family members to remove any weapons or hazardous conditions from the patient’s home.
Including the family in problem-solving is especially important when managing older suicidal patients. For patients who are isolated from family or friends, recovery may depend on improving their support network.
Table 3
Comparing screening instruments for suicide risk
| Measure | Description | Time (minutes) |
|---|---|---|
| Beck Depression Inventory (BDI) | 21-item, self-administered; identifies depressive symptoms in past week | 10 |
| Beck Hopelessness Scale (BHS) | 20-item, self-administered; measures hopelessness, fatalism, and pessimism in past week | 5 |
| Beck Scale for Suicide Ideation-Current (SSI-C) | 19-item, self-administered; gauges suicidal intention | 10 |
| Hamilton Rating Scale for Depression-revised (HRSD-R) | 21-item, clinician-administered; rates depressive symptoms in past week | 25 |
Outpatient care. Not all acutely suicidal older patients require hospital admission. They may be safely managed as outpatients if they:
- have strong social support
- are not isolated
- have no access to firearms or other dangerous weapons.
Safety can be enhanced by having family members take responsibility for the senior’s well-being and by asking the patient to contract for safety. A safety contract may include:
- verbal confirmation—and ideally a written statement—that the patient will not commit suicide within a specified period
- a list of people the patient will contact when feeling suicidal
- steps being taken to monitor the patient’s welfare.
Finally, schedule follow-up appointments soon after discharge to certify patients are being closely monitored. To encourage outpatient medication adherence, build strong alliances with family members and ask patients to bring in their pill bottles during follow-up appointments.
CASE REPORT continued: Observation begins
The staff is clearly concerned about Mr. V’s suicide risk and requests that he voluntarily admit himself to the VA hospital. This decision is based on his level of isolation, the lethality of his suicide plan, access to a weapon, and the depression and hopelessness revealed by his screening tests. He reluctantly agrees and is admitted to the inpatient psychiatric unit for observation and treatment by a geriatric internist and a geriatric psychiatrist.
DRUG THERAPY FOR SUICIDALITY
For patients with mild depressive symptoms, psychotherapy may be sufficient to manage depression associated with suicidality. However, those with moderate-to-severe depression require both drug treatment and psychotherapy.
Drug selection depends upon the underlying psychiatric illness. If the older patient is experiencing a depressive disorder, a selective serotonin reuptake inhibitor (SSRI) or another antidepressant could serve as first-line treatment (Table 4). These medications are safe for suicidal patients because they are not fatal in overdose.
Administration. Because age-related changes in pharmacokinetics and spharmacodynamics can slow medication clearance, reduced dosages usually achieve a therapeutic effect and minimize the risk of side effects in geriatric patients.
Antidepressants commonly used for older patients are shown in Table 4. Excepting citalopram and escitalopram, these dosages are lower than usual. We start healthy older patients on one-half the usual dosage and those who are medically ill or have neurodegenerative disorders on one-third to one-fourth the usual dosage. We also titrate more slowly to reduce the risk of side effects.
Table 4
Antidepressants commonly used to treat geriatric depression
| Medication | Recommended dosage (mg/d) |
|---|---|
| SSRIs | |
| Citalopram | 20 to 40 |
| Escitalopram | 10 to 20 |
| Fluoxetine | 10 to 40 |
| Paroxetine | 10 to 40 |
| Sertraline | 25 to 150 |
| Others | |
| Bupropion | 100 to 400 |
| Mirtazapine | 15 to 45 |
| Venlafaxine | 75 to 225 |
As in younger patients, the most common side effects of SSRIs in older patients include GI difficulties, overactivation, and sexual dysfunction. Paroxetine’s potential for anticholinergic effects may be a concern for some older patients.
Drug-drug interactions are of great concern when treating older patients, who take an average of six to nine medications per day.17 Compared with other SSRIs, fluoxetine and paroxetine, are more likely to inhibit cytochrome P-450 enzymes 2D6 and 3A4. They could thus increase blood levels of drugs taken concomitantly that are substrates of 2D6 or 3A4.
Antidepressant side effects can sometimes be used to advantage. For example, mirtazapine’s sedating property at lower dosages could help older patients with insomnia.
CASE REPORT concluded: Finding support
Mr. V is started on an SSRI antidepressant. He also receives supportive and milieu therapy and coping skills training. During his hospitalization, Mr. V contracts for safety and allows his sister to remove the handgun from his home.
Upon discharge, Mr. V is referred to a day treatment program that operates 3 to 5 days a week and offers case management, group therapy, and individual psychotherapy. The program helps him meet other older patients and allows him to discuss his life’s accomplishments and losses with others his age. His sister is an integral part of the program, and he maintains close contact with her.
Mr. V reports vague and occasional suicidal ideation, with no specific plan or intent. He and his sister note that his medical condition improved soon after his psychiatric condition stabilized.
Related resources
- Surgeon General’s Call to Action to Prevent Suicide. www.mental-health.org/suicideprevention/calltoaction.pdf
- Centers for Disease Control and Prevention. National Center for Injury Prevention and Control.
Drug brand names
- Bupropion • Wellbutrin
- Citalopram • Celexa
- Escitalopram • Lexapro
- Fluoxetine • Prozac
- Mirtazapine • Remeron
- Paroxetine • Paxil
- Sertraline • Zoloft
- Venlafaxine • Effexor
Disclosure
Drs. Montross reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Mohamed is a speaker and consultant to Forest Laboratories and Eli Lilly and Co.
Dr. Kasckow receives research support from, is a consultant to, and is a speaker for Forest Laboratories, Eli Lilly and Co., Pfizer Inc., and Janssen Pharmaceutica.
Dr. Zisook is a consultant to GlaxoSmithKline and a speaker for GlaxoSmithKline, Wyeth Pharmaceuticals, Pfizer Inc., Forest Laboratories, and Bristol-Myers Squibb Co.
1. Centers for Disease Control and Prevention. Surveillance for Injuries and Violence Among Older Adults (CDC Surveillance Summary, December 17, 1999, Chap. 3:27-50). www.cdc.gov/mmwr/PDF/SS/SS4808.pdf
2. Kaplan HI, Sadock BJ. Synopsis of psychiatry (6th ed). Baltimore: Williams & Wilkins, 1991.
3. Lyon DE, Chase LS, Farrell SP. Using an interview guide to assess suicidal ideation. Nurse Practitioner 2002;27:26-31.
4. Conwell Y, Lyness JM, Duberstein P, et al. Completed suicide among older patients in primary care practices: A controlled study. J Am Geriatr Soc 2000;48:23-9.
5. Conwell Y, Duberstein PR, Cox C, et al. Relationships of age and Axis I diagnoses in victims of completed suicide: A psychological autopsy study. Am J Psychiatry 1996;153:1001-8.
6. Harwood D, Hawton K, Hope T, Jacoby R. Psychiatric disorder and personality factors associated with suicide in older people: A descriptive and case-control study. Int J Geriatr Psychiatry 2001;16:155-65.
7. Henriksson MM, Marttunen MJ, Isometsa ET, et al. Mental disorders in elderly suicide. Int Psychogeriatr 1995;7:275-86.
8. Conwell Y, Duberstein PR, Caine ED. Risk factors for suicide in later life. Biol Psychiatry 2002;52:193-204.
9. Beck AT, Brown GK, Steer RA. Psychometric characteristics of the Scale for Suicide Ideation with psychiatric outpatients. Behav Res Ther 1997;35:1039-46.
10. Beck AT, Steer RA. Manual for the Beck Depression Inventory. San Antonio, TX: The Psychological Corporation, 1987.
11. Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression Inventory: Twenty-five years later. Clin Psychol Rev 1988;8:77-100.
12. Beck AT, Weissman A, Lester D, Trexler L. The measurement of pessimism: The hopelessness scale. J Consult Clin Psychol 1974;42:861-5.
13. Drake RE, Cotton PG. Depression, hopelessness and suicide in chronic schizophrenia. Br J Psychiatry 1986;148:554-9.
14. Beck AT, Steer RA, Kovacs M, Garrison B. Hopelessness and eventual suicide: A 10-year perspective study of patients hospitalized with suicidal ideation. Am J Psychiatry 1985;142:559-63.
15. Riskind JH, Beck AT, Brown G, Steer RA. Taking the measure of anxiety and depression: Validity of the reconstructed Hamilton Scales. J Nerv Ment Dis 1987;175:474-9.
16. Lamberg L. Psychiatric emergencies call for comprehensive assessment and treatment. JAMA 2002;288:686-7.
17. Sadavoy J, Lazarus LW, Jarvik LF. Grossberg GT (eds). Comprehensive review of geriatric psychiatry (2nd ed). Washington, DC: American Psychiatric Press, 1996.
CASE REPORT: I have a gun
Mr. V, age 77, appears depressed and anxious during his appointment at a mental hygiene clinic. He reports insomnia, concentration trouble, and anhedonia. He tells the psychiatrist he keeps a loaded gun at home and is not sure he can control his suicidal impulses.
The patient is Caucasian and has a history of heart failure, pulmonary disease, and type 2 diabetes. His wife died 18 months ago. He lives alone, but his sister lives nearby. He recently received a right hip replacement, which required 3 months of rehabilitation in a nursing home to recover from surgical complications. He still has trouble walking.
As in Mr. V’s case, treating older patients referred for psychiatric care often involves evaluating suicide risk. His age, race, gender, depressed mood, recent bereavement, and medical ailments place him in the population at highest risk of suicide (Box, Table 1).1-8
Approximately 20% of all suicides in the United States are committed by persons age 65 or older,1 who account for 13% of the total population. The suicide rate among persons older than 75 is three times higher than it is for the young.2 Older Caucasian men have the highest per-capita rate of completed suicide, compared with any other group of Americans.3
Psychiatric disorders. The rates of Axis I disorders among older persons who commit suicide fall within the average range for all age groups (70 to 90%). However, the types of disorders seen in the older population differ from those of younger suicides (Table 1).4-8
Affective illness has been termed “the predominant psychopathology associated with suicide in later life.”4 Among older persons who commit suicide, three-fourths (76%) have diagnosable mood disorders4 and nearly two-thirds (63%) have depression.6 Contributing risk factors include alcoholism and substance abuse,4,6,7 Axis II disorders, and dementia.6
Losses and medical illness. In later life, bereavement, loss of independence, or financial reversals may lead to depression. Older persons who take their own lives also tend to have greater physical health burdens and more functional disabilities than those who do not commit suicide.6,8
This article describes an age-based psychiatric workup of the suicidal older patient, including factors to consider when screening for depressive symptoms, prescribing drug therapy, and determining the need for hospitalization.
AGE-BASED CLINICAL WORKUP
For older patients who report suicidal ideation, an age-appropriate workup—using clinical interviews and screening instruments—is essential. The clinical interview can build rapport and gather information about the patient’s suicidal plan or intent. Based on our experience, we recommend the following 6-step screening interview, summarized in Table 2.
- Ask about a specific plan. Does the patient have the means readily available to carry out this plan? What is the timeline (imminent versus vaguely futuristic)? Does the patient report having control over this plan?
- Gather a suicide history. Has the patient attempted suicide before? By what means? Is there a family history of suicide? If yes, by what means did this family member commit suicide, and how was the patient affected?
- Assess social status. How isolated is the patient? Have there been recent changes in his or her social circle, such as loss of a spouse? Can the patient identify at least one person who would be negatively affected by the suicide?
- Assess medical health. Does the patient suffer from chronic pain? Does the patient have a recently diagnosed medical condition? Has a longstanding medical condition become more debilitating? Does the patient report feeling hopeless about impending medical difficulties? Has he or she been keeping regularly scheduled medical appointments with outpatient clinicians?
- Assess mental health. Does the patient meet DSM-IV criteria for depression or schizophrenia, which are associated with high suicide risk? Does he or she report being hopeless or helpless? Is the suicidal ideation ego dystonic?
- Ascertain clinical signs of suicidal intent. Has the patient:
Table 1
Suicide risk with mental and physical illness, by patient age
| Risk factors | Young (21 to 34 yrs) | Middle-aged (35 to 54 yrs) | Young-old (55 to 74 yrs) | Elderly (77+ yrs) |
|---|---|---|---|---|
| Psychiatric disorders | • | • | • | • |
| Mood disorders | ○ | • | • | |
| Alcohol abuse | ○ | • | ○ | |
| Primary psychoses | • | ○ | ||
| Personality disorders | ○ | |||
| Physical ailments | • | • | ||
| • Significant risk factor ○ Potential risk factor | ||||
| Source: Compiled from information in references 4-8. | ||||
CASE REPORT continued: Some telling signs
Mr. V’s laboratory screening reveals slightly elevated serum glucose and mild anemia. An ECG reveals a type I heart block, but all other lab results are unremarkable. His sister reports he recently gave away his dog, which he and his wife had owned for many years. He has also mentioned a desire to revise his will when speaking to other family members. Hospital records indicate he has missed numerous medical appointments over the past 4 months.
SCREENING INSTRUMENTS
Psychological assessments can often buttress the clinical interview findings. Several measurements are well-suited for detecting suicidal risk and concomitant depression (Table 3).
Beck SSI-C. The Beck Scale for Suicide Ideation – Current (SSI-C) assesses a patient’s preparation and motivation to commit suicide.9 This short (19-item) self-report measure asks patients to rate their wish to die, desire to attempt suicide, duration (and frequency) of suicidal thoughts, sense of control over suicide, and deterrents they face. The SSI-C helps to measure or monitor suicidality and is reliable and valid for psychiatric outpatients.9
BDI-II. The Beck Depression Inventory—recently revised in a second edition (BDI-II)10—can be useful because depression is one of the strongest risk factors for elder suicide. The 21-item BDI-II—a psychometrically sound, self-report instrument—asks about general symptoms of depression and gauges their severity. It can be applied to diverse patient populations and ages11 and is appropriate for older patients who are also being treated medically.
Beck Hopelessness Scale. Hopelessness has been recognized as a possible harbinger of suicide.12 One study showed that depression became a clinically meaningful suicide predictor only when accompanied by hopelessness.13
A score of 10 or more on the Beck Hopelessness Scale identified 91% of patients in one study who eventually committed suicide. The hopelessness patients expressed on this scale more strongly differentiated between those who did or did not commit suicide than did their scores on the BDI or SSI-C.14
Table 2
6-step clinical interview with an older suicidal patient
|
|
| Source: Adapted from the Cincinnati Veterans Affairs Medical Center general psychological suicide assessment |
HRSD-R. The revised Hamilton Rating Scale for Depression (HRSD-R) documents patients’ levels of mood disturbance and suicidality. One item in this 21-item, clinician-administered instrument specifically asks about the patient’s level of suicidality in the past week. The scale has well-documented reliability and validity and is appropriate for psychiatric populations.15
CASE REPORT continued: Alarming findings
Along with the clinical interview, Mr. V. is screened with the Beck Hopelessness Scale and Beck Depression Inventory-II. These instruments are chosen because they are easy to administer, and patients can readily comprehend the questions—even when under duress. Mr. V’s results reveal moderate depression and severe hopelessness.
INPATIENT VS. OUTPATIENT CARE
Older patients are often referred to a psychiatrist because of vague suicidal ideation, but they may also present in an acute crisis—with immediate plans for suicide and readily accessible means. The first concern for their safety is to ensure they are not left alone.
Patient interview. First, listen empathetically and ask detailed questions, especially ones that remind patients of their daily connections and responsibilities. For instance, ask, “Do you have children who would be affected by your decision?” Address patients’ immediate needs, such as hunger, thirst, or pain.16 Work on building a therapeutic alliance before asking questions that may appear trivial to agitated patients (such as tasks assessing cognitive abilities).
Avoid arguing with patients, and refrain from offering advice or sermonizing. Allow them to describe their emotions, and communicate that you understand their concerns. Discuss how they can expect to receive treatment to ease their discomfort. Inform them that mental health specialists can treat them and monitor their progress.
Hospitalization. Begin discussing treatment options and broach the notion of hospital admission if necessary. One way to foster an alliance is to frame inpatient care as a way of helping them recover from their crisis in a safe environment.
To ensure patient safety, it is best to err on the side of admission. Admitting the suicidal patient not only guarantees strict supervision but also allows time for necessary psychological assessment. Hospitalization may also allow family members to remove any weapons or hazardous conditions from the patient’s home.
Including the family in problem-solving is especially important when managing older suicidal patients. For patients who are isolated from family or friends, recovery may depend on improving their support network.
Table 3
Comparing screening instruments for suicide risk
| Measure | Description | Time (minutes) |
|---|---|---|
| Beck Depression Inventory (BDI) | 21-item, self-administered; identifies depressive symptoms in past week | 10 |
| Beck Hopelessness Scale (BHS) | 20-item, self-administered; measures hopelessness, fatalism, and pessimism in past week | 5 |
| Beck Scale for Suicide Ideation-Current (SSI-C) | 19-item, self-administered; gauges suicidal intention | 10 |
| Hamilton Rating Scale for Depression-revised (HRSD-R) | 21-item, clinician-administered; rates depressive symptoms in past week | 25 |
Outpatient care. Not all acutely suicidal older patients require hospital admission. They may be safely managed as outpatients if they:
- have strong social support
- are not isolated
- have no access to firearms or other dangerous weapons.
Safety can be enhanced by having family members take responsibility for the senior’s well-being and by asking the patient to contract for safety. A safety contract may include:
- verbal confirmation—and ideally a written statement—that the patient will not commit suicide within a specified period
- a list of people the patient will contact when feeling suicidal
- steps being taken to monitor the patient’s welfare.
Finally, schedule follow-up appointments soon after discharge to certify patients are being closely monitored. To encourage outpatient medication adherence, build strong alliances with family members and ask patients to bring in their pill bottles during follow-up appointments.
CASE REPORT continued: Observation begins
The staff is clearly concerned about Mr. V’s suicide risk and requests that he voluntarily admit himself to the VA hospital. This decision is based on his level of isolation, the lethality of his suicide plan, access to a weapon, and the depression and hopelessness revealed by his screening tests. He reluctantly agrees and is admitted to the inpatient psychiatric unit for observation and treatment by a geriatric internist and a geriatric psychiatrist.
DRUG THERAPY FOR SUICIDALITY
For patients with mild depressive symptoms, psychotherapy may be sufficient to manage depression associated with suicidality. However, those with moderate-to-severe depression require both drug treatment and psychotherapy.
Drug selection depends upon the underlying psychiatric illness. If the older patient is experiencing a depressive disorder, a selective serotonin reuptake inhibitor (SSRI) or another antidepressant could serve as first-line treatment (Table 4). These medications are safe for suicidal patients because they are not fatal in overdose.
Administration. Because age-related changes in pharmacokinetics and spharmacodynamics can slow medication clearance, reduced dosages usually achieve a therapeutic effect and minimize the risk of side effects in geriatric patients.
Antidepressants commonly used for older patients are shown in Table 4. Excepting citalopram and escitalopram, these dosages are lower than usual. We start healthy older patients on one-half the usual dosage and those who are medically ill or have neurodegenerative disorders on one-third to one-fourth the usual dosage. We also titrate more slowly to reduce the risk of side effects.
Table 4
Antidepressants commonly used to treat geriatric depression
| Medication | Recommended dosage (mg/d) |
|---|---|
| SSRIs | |
| Citalopram | 20 to 40 |
| Escitalopram | 10 to 20 |
| Fluoxetine | 10 to 40 |
| Paroxetine | 10 to 40 |
| Sertraline | 25 to 150 |
| Others | |
| Bupropion | 100 to 400 |
| Mirtazapine | 15 to 45 |
| Venlafaxine | 75 to 225 |
As in younger patients, the most common side effects of SSRIs in older patients include GI difficulties, overactivation, and sexual dysfunction. Paroxetine’s potential for anticholinergic effects may be a concern for some older patients.
Drug-drug interactions are of great concern when treating older patients, who take an average of six to nine medications per day.17 Compared with other SSRIs, fluoxetine and paroxetine, are more likely to inhibit cytochrome P-450 enzymes 2D6 and 3A4. They could thus increase blood levels of drugs taken concomitantly that are substrates of 2D6 or 3A4.
Antidepressant side effects can sometimes be used to advantage. For example, mirtazapine’s sedating property at lower dosages could help older patients with insomnia.
CASE REPORT concluded: Finding support
Mr. V is started on an SSRI antidepressant. He also receives supportive and milieu therapy and coping skills training. During his hospitalization, Mr. V contracts for safety and allows his sister to remove the handgun from his home.
Upon discharge, Mr. V is referred to a day treatment program that operates 3 to 5 days a week and offers case management, group therapy, and individual psychotherapy. The program helps him meet other older patients and allows him to discuss his life’s accomplishments and losses with others his age. His sister is an integral part of the program, and he maintains close contact with her.
Mr. V reports vague and occasional suicidal ideation, with no specific plan or intent. He and his sister note that his medical condition improved soon after his psychiatric condition stabilized.
Related resources
- Surgeon General’s Call to Action to Prevent Suicide. www.mental-health.org/suicideprevention/calltoaction.pdf
- Centers for Disease Control and Prevention. National Center for Injury Prevention and Control.
Drug brand names
- Bupropion • Wellbutrin
- Citalopram • Celexa
- Escitalopram • Lexapro
- Fluoxetine • Prozac
- Mirtazapine • Remeron
- Paroxetine • Paxil
- Sertraline • Zoloft
- Venlafaxine • Effexor
Disclosure
Drs. Montross reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Mohamed is a speaker and consultant to Forest Laboratories and Eli Lilly and Co.
Dr. Kasckow receives research support from, is a consultant to, and is a speaker for Forest Laboratories, Eli Lilly and Co., Pfizer Inc., and Janssen Pharmaceutica.
Dr. Zisook is a consultant to GlaxoSmithKline and a speaker for GlaxoSmithKline, Wyeth Pharmaceuticals, Pfizer Inc., Forest Laboratories, and Bristol-Myers Squibb Co.
CASE REPORT: I have a gun
Mr. V, age 77, appears depressed and anxious during his appointment at a mental hygiene clinic. He reports insomnia, concentration trouble, and anhedonia. He tells the psychiatrist he keeps a loaded gun at home and is not sure he can control his suicidal impulses.
The patient is Caucasian and has a history of heart failure, pulmonary disease, and type 2 diabetes. His wife died 18 months ago. He lives alone, but his sister lives nearby. He recently received a right hip replacement, which required 3 months of rehabilitation in a nursing home to recover from surgical complications. He still has trouble walking.
As in Mr. V’s case, treating older patients referred for psychiatric care often involves evaluating suicide risk. His age, race, gender, depressed mood, recent bereavement, and medical ailments place him in the population at highest risk of suicide (Box, Table 1).1-8
Approximately 20% of all suicides in the United States are committed by persons age 65 or older,1 who account for 13% of the total population. The suicide rate among persons older than 75 is three times higher than it is for the young.2 Older Caucasian men have the highest per-capita rate of completed suicide, compared with any other group of Americans.3
Psychiatric disorders. The rates of Axis I disorders among older persons who commit suicide fall within the average range for all age groups (70 to 90%). However, the types of disorders seen in the older population differ from those of younger suicides (Table 1).4-8
Affective illness has been termed “the predominant psychopathology associated with suicide in later life.”4 Among older persons who commit suicide, three-fourths (76%) have diagnosable mood disorders4 and nearly two-thirds (63%) have depression.6 Contributing risk factors include alcoholism and substance abuse,4,6,7 Axis II disorders, and dementia.6
Losses and medical illness. In later life, bereavement, loss of independence, or financial reversals may lead to depression. Older persons who take their own lives also tend to have greater physical health burdens and more functional disabilities than those who do not commit suicide.6,8
This article describes an age-based psychiatric workup of the suicidal older patient, including factors to consider when screening for depressive symptoms, prescribing drug therapy, and determining the need for hospitalization.
AGE-BASED CLINICAL WORKUP
For older patients who report suicidal ideation, an age-appropriate workup—using clinical interviews and screening instruments—is essential. The clinical interview can build rapport and gather information about the patient’s suicidal plan or intent. Based on our experience, we recommend the following 6-step screening interview, summarized in Table 2.
- Ask about a specific plan. Does the patient have the means readily available to carry out this plan? What is the timeline (imminent versus vaguely futuristic)? Does the patient report having control over this plan?
- Gather a suicide history. Has the patient attempted suicide before? By what means? Is there a family history of suicide? If yes, by what means did this family member commit suicide, and how was the patient affected?
- Assess social status. How isolated is the patient? Have there been recent changes in his or her social circle, such as loss of a spouse? Can the patient identify at least one person who would be negatively affected by the suicide?
- Assess medical health. Does the patient suffer from chronic pain? Does the patient have a recently diagnosed medical condition? Has a longstanding medical condition become more debilitating? Does the patient report feeling hopeless about impending medical difficulties? Has he or she been keeping regularly scheduled medical appointments with outpatient clinicians?
- Assess mental health. Does the patient meet DSM-IV criteria for depression or schizophrenia, which are associated with high suicide risk? Does he or she report being hopeless or helpless? Is the suicidal ideation ego dystonic?
- Ascertain clinical signs of suicidal intent. Has the patient:
Table 1
Suicide risk with mental and physical illness, by patient age
| Risk factors | Young (21 to 34 yrs) | Middle-aged (35 to 54 yrs) | Young-old (55 to 74 yrs) | Elderly (77+ yrs) |
|---|---|---|---|---|
| Psychiatric disorders | • | • | • | • |
| Mood disorders | ○ | • | • | |
| Alcohol abuse | ○ | • | ○ | |
| Primary psychoses | • | ○ | ||
| Personality disorders | ○ | |||
| Physical ailments | • | • | ||
| • Significant risk factor ○ Potential risk factor | ||||
| Source: Compiled from information in references 4-8. | ||||
CASE REPORT continued: Some telling signs
Mr. V’s laboratory screening reveals slightly elevated serum glucose and mild anemia. An ECG reveals a type I heart block, but all other lab results are unremarkable. His sister reports he recently gave away his dog, which he and his wife had owned for many years. He has also mentioned a desire to revise his will when speaking to other family members. Hospital records indicate he has missed numerous medical appointments over the past 4 months.
SCREENING INSTRUMENTS
Psychological assessments can often buttress the clinical interview findings. Several measurements are well-suited for detecting suicidal risk and concomitant depression (Table 3).
Beck SSI-C. The Beck Scale for Suicide Ideation – Current (SSI-C) assesses a patient’s preparation and motivation to commit suicide.9 This short (19-item) self-report measure asks patients to rate their wish to die, desire to attempt suicide, duration (and frequency) of suicidal thoughts, sense of control over suicide, and deterrents they face. The SSI-C helps to measure or monitor suicidality and is reliable and valid for psychiatric outpatients.9
BDI-II. The Beck Depression Inventory—recently revised in a second edition (BDI-II)10—can be useful because depression is one of the strongest risk factors for elder suicide. The 21-item BDI-II—a psychometrically sound, self-report instrument—asks about general symptoms of depression and gauges their severity. It can be applied to diverse patient populations and ages11 and is appropriate for older patients who are also being treated medically.
Beck Hopelessness Scale. Hopelessness has been recognized as a possible harbinger of suicide.12 One study showed that depression became a clinically meaningful suicide predictor only when accompanied by hopelessness.13
A score of 10 or more on the Beck Hopelessness Scale identified 91% of patients in one study who eventually committed suicide. The hopelessness patients expressed on this scale more strongly differentiated between those who did or did not commit suicide than did their scores on the BDI or SSI-C.14
Table 2
6-step clinical interview with an older suicidal patient
|
|
| Source: Adapted from the Cincinnati Veterans Affairs Medical Center general psychological suicide assessment |
HRSD-R. The revised Hamilton Rating Scale for Depression (HRSD-R) documents patients’ levels of mood disturbance and suicidality. One item in this 21-item, clinician-administered instrument specifically asks about the patient’s level of suicidality in the past week. The scale has well-documented reliability and validity and is appropriate for psychiatric populations.15
CASE REPORT continued: Alarming findings
Along with the clinical interview, Mr. V. is screened with the Beck Hopelessness Scale and Beck Depression Inventory-II. These instruments are chosen because they are easy to administer, and patients can readily comprehend the questions—even when under duress. Mr. V’s results reveal moderate depression and severe hopelessness.
INPATIENT VS. OUTPATIENT CARE
Older patients are often referred to a psychiatrist because of vague suicidal ideation, but they may also present in an acute crisis—with immediate plans for suicide and readily accessible means. The first concern for their safety is to ensure they are not left alone.
Patient interview. First, listen empathetically and ask detailed questions, especially ones that remind patients of their daily connections and responsibilities. For instance, ask, “Do you have children who would be affected by your decision?” Address patients’ immediate needs, such as hunger, thirst, or pain.16 Work on building a therapeutic alliance before asking questions that may appear trivial to agitated patients (such as tasks assessing cognitive abilities).
Avoid arguing with patients, and refrain from offering advice or sermonizing. Allow them to describe their emotions, and communicate that you understand their concerns. Discuss how they can expect to receive treatment to ease their discomfort. Inform them that mental health specialists can treat them and monitor their progress.
Hospitalization. Begin discussing treatment options and broach the notion of hospital admission if necessary. One way to foster an alliance is to frame inpatient care as a way of helping them recover from their crisis in a safe environment.
To ensure patient safety, it is best to err on the side of admission. Admitting the suicidal patient not only guarantees strict supervision but also allows time for necessary psychological assessment. Hospitalization may also allow family members to remove any weapons or hazardous conditions from the patient’s home.
Including the family in problem-solving is especially important when managing older suicidal patients. For patients who are isolated from family or friends, recovery may depend on improving their support network.
Table 3
Comparing screening instruments for suicide risk
| Measure | Description | Time (minutes) |
|---|---|---|
| Beck Depression Inventory (BDI) | 21-item, self-administered; identifies depressive symptoms in past week | 10 |
| Beck Hopelessness Scale (BHS) | 20-item, self-administered; measures hopelessness, fatalism, and pessimism in past week | 5 |
| Beck Scale for Suicide Ideation-Current (SSI-C) | 19-item, self-administered; gauges suicidal intention | 10 |
| Hamilton Rating Scale for Depression-revised (HRSD-R) | 21-item, clinician-administered; rates depressive symptoms in past week | 25 |
Outpatient care. Not all acutely suicidal older patients require hospital admission. They may be safely managed as outpatients if they:
- have strong social support
- are not isolated
- have no access to firearms or other dangerous weapons.
Safety can be enhanced by having family members take responsibility for the senior’s well-being and by asking the patient to contract for safety. A safety contract may include:
- verbal confirmation—and ideally a written statement—that the patient will not commit suicide within a specified period
- a list of people the patient will contact when feeling suicidal
- steps being taken to monitor the patient’s welfare.
Finally, schedule follow-up appointments soon after discharge to certify patients are being closely monitored. To encourage outpatient medication adherence, build strong alliances with family members and ask patients to bring in their pill bottles during follow-up appointments.
CASE REPORT continued: Observation begins
The staff is clearly concerned about Mr. V’s suicide risk and requests that he voluntarily admit himself to the VA hospital. This decision is based on his level of isolation, the lethality of his suicide plan, access to a weapon, and the depression and hopelessness revealed by his screening tests. He reluctantly agrees and is admitted to the inpatient psychiatric unit for observation and treatment by a geriatric internist and a geriatric psychiatrist.
DRUG THERAPY FOR SUICIDALITY
For patients with mild depressive symptoms, psychotherapy may be sufficient to manage depression associated with suicidality. However, those with moderate-to-severe depression require both drug treatment and psychotherapy.
Drug selection depends upon the underlying psychiatric illness. If the older patient is experiencing a depressive disorder, a selective serotonin reuptake inhibitor (SSRI) or another antidepressant could serve as first-line treatment (Table 4). These medications are safe for suicidal patients because they are not fatal in overdose.
Administration. Because age-related changes in pharmacokinetics and spharmacodynamics can slow medication clearance, reduced dosages usually achieve a therapeutic effect and minimize the risk of side effects in geriatric patients.
Antidepressants commonly used for older patients are shown in Table 4. Excepting citalopram and escitalopram, these dosages are lower than usual. We start healthy older patients on one-half the usual dosage and those who are medically ill or have neurodegenerative disorders on one-third to one-fourth the usual dosage. We also titrate more slowly to reduce the risk of side effects.
Table 4
Antidepressants commonly used to treat geriatric depression
| Medication | Recommended dosage (mg/d) |
|---|---|
| SSRIs | |
| Citalopram | 20 to 40 |
| Escitalopram | 10 to 20 |
| Fluoxetine | 10 to 40 |
| Paroxetine | 10 to 40 |
| Sertraline | 25 to 150 |
| Others | |
| Bupropion | 100 to 400 |
| Mirtazapine | 15 to 45 |
| Venlafaxine | 75 to 225 |
As in younger patients, the most common side effects of SSRIs in older patients include GI difficulties, overactivation, and sexual dysfunction. Paroxetine’s potential for anticholinergic effects may be a concern for some older patients.
Drug-drug interactions are of great concern when treating older patients, who take an average of six to nine medications per day.17 Compared with other SSRIs, fluoxetine and paroxetine, are more likely to inhibit cytochrome P-450 enzymes 2D6 and 3A4. They could thus increase blood levels of drugs taken concomitantly that are substrates of 2D6 or 3A4.
Antidepressant side effects can sometimes be used to advantage. For example, mirtazapine’s sedating property at lower dosages could help older patients with insomnia.
CASE REPORT concluded: Finding support
Mr. V is started on an SSRI antidepressant. He also receives supportive and milieu therapy and coping skills training. During his hospitalization, Mr. V contracts for safety and allows his sister to remove the handgun from his home.
Upon discharge, Mr. V is referred to a day treatment program that operates 3 to 5 days a week and offers case management, group therapy, and individual psychotherapy. The program helps him meet other older patients and allows him to discuss his life’s accomplishments and losses with others his age. His sister is an integral part of the program, and he maintains close contact with her.
Mr. V reports vague and occasional suicidal ideation, with no specific plan or intent. He and his sister note that his medical condition improved soon after his psychiatric condition stabilized.
Related resources
- Surgeon General’s Call to Action to Prevent Suicide. www.mental-health.org/suicideprevention/calltoaction.pdf
- Centers for Disease Control and Prevention. National Center for Injury Prevention and Control.
Drug brand names
- Bupropion • Wellbutrin
- Citalopram • Celexa
- Escitalopram • Lexapro
- Fluoxetine • Prozac
- Mirtazapine • Remeron
- Paroxetine • Paxil
- Sertraline • Zoloft
- Venlafaxine • Effexor
Disclosure
Drs. Montross reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Mohamed is a speaker and consultant to Forest Laboratories and Eli Lilly and Co.
Dr. Kasckow receives research support from, is a consultant to, and is a speaker for Forest Laboratories, Eli Lilly and Co., Pfizer Inc., and Janssen Pharmaceutica.
Dr. Zisook is a consultant to GlaxoSmithKline and a speaker for GlaxoSmithKline, Wyeth Pharmaceuticals, Pfizer Inc., Forest Laboratories, and Bristol-Myers Squibb Co.
1. Centers for Disease Control and Prevention. Surveillance for Injuries and Violence Among Older Adults (CDC Surveillance Summary, December 17, 1999, Chap. 3:27-50). www.cdc.gov/mmwr/PDF/SS/SS4808.pdf
2. Kaplan HI, Sadock BJ. Synopsis of psychiatry (6th ed). Baltimore: Williams & Wilkins, 1991.
3. Lyon DE, Chase LS, Farrell SP. Using an interview guide to assess suicidal ideation. Nurse Practitioner 2002;27:26-31.
4. Conwell Y, Lyness JM, Duberstein P, et al. Completed suicide among older patients in primary care practices: A controlled study. J Am Geriatr Soc 2000;48:23-9.
5. Conwell Y, Duberstein PR, Cox C, et al. Relationships of age and Axis I diagnoses in victims of completed suicide: A psychological autopsy study. Am J Psychiatry 1996;153:1001-8.
6. Harwood D, Hawton K, Hope T, Jacoby R. Psychiatric disorder and personality factors associated with suicide in older people: A descriptive and case-control study. Int J Geriatr Psychiatry 2001;16:155-65.
7. Henriksson MM, Marttunen MJ, Isometsa ET, et al. Mental disorders in elderly suicide. Int Psychogeriatr 1995;7:275-86.
8. Conwell Y, Duberstein PR, Caine ED. Risk factors for suicide in later life. Biol Psychiatry 2002;52:193-204.
9. Beck AT, Brown GK, Steer RA. Psychometric characteristics of the Scale for Suicide Ideation with psychiatric outpatients. Behav Res Ther 1997;35:1039-46.
10. Beck AT, Steer RA. Manual for the Beck Depression Inventory. San Antonio, TX: The Psychological Corporation, 1987.
11. Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression Inventory: Twenty-five years later. Clin Psychol Rev 1988;8:77-100.
12. Beck AT, Weissman A, Lester D, Trexler L. The measurement of pessimism: The hopelessness scale. J Consult Clin Psychol 1974;42:861-5.
13. Drake RE, Cotton PG. Depression, hopelessness and suicide in chronic schizophrenia. Br J Psychiatry 1986;148:554-9.
14. Beck AT, Steer RA, Kovacs M, Garrison B. Hopelessness and eventual suicide: A 10-year perspective study of patients hospitalized with suicidal ideation. Am J Psychiatry 1985;142:559-63.
15. Riskind JH, Beck AT, Brown G, Steer RA. Taking the measure of anxiety and depression: Validity of the reconstructed Hamilton Scales. J Nerv Ment Dis 1987;175:474-9.
16. Lamberg L. Psychiatric emergencies call for comprehensive assessment and treatment. JAMA 2002;288:686-7.
17. Sadavoy J, Lazarus LW, Jarvik LF. Grossberg GT (eds). Comprehensive review of geriatric psychiatry (2nd ed). Washington, DC: American Psychiatric Press, 1996.
1. Centers for Disease Control and Prevention. Surveillance for Injuries and Violence Among Older Adults (CDC Surveillance Summary, December 17, 1999, Chap. 3:27-50). www.cdc.gov/mmwr/PDF/SS/SS4808.pdf
2. Kaplan HI, Sadock BJ. Synopsis of psychiatry (6th ed). Baltimore: Williams & Wilkins, 1991.
3. Lyon DE, Chase LS, Farrell SP. Using an interview guide to assess suicidal ideation. Nurse Practitioner 2002;27:26-31.
4. Conwell Y, Lyness JM, Duberstein P, et al. Completed suicide among older patients in primary care practices: A controlled study. J Am Geriatr Soc 2000;48:23-9.
5. Conwell Y, Duberstein PR, Cox C, et al. Relationships of age and Axis I diagnoses in victims of completed suicide: A psychological autopsy study. Am J Psychiatry 1996;153:1001-8.
6. Harwood D, Hawton K, Hope T, Jacoby R. Psychiatric disorder and personality factors associated with suicide in older people: A descriptive and case-control study. Int J Geriatr Psychiatry 2001;16:155-65.
7. Henriksson MM, Marttunen MJ, Isometsa ET, et al. Mental disorders in elderly suicide. Int Psychogeriatr 1995;7:275-86.
8. Conwell Y, Duberstein PR, Caine ED. Risk factors for suicide in later life. Biol Psychiatry 2002;52:193-204.
9. Beck AT, Brown GK, Steer RA. Psychometric characteristics of the Scale for Suicide Ideation with psychiatric outpatients. Behav Res Ther 1997;35:1039-46.
10. Beck AT, Steer RA. Manual for the Beck Depression Inventory. San Antonio, TX: The Psychological Corporation, 1987.
11. Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression Inventory: Twenty-five years later. Clin Psychol Rev 1988;8:77-100.
12. Beck AT, Weissman A, Lester D, Trexler L. The measurement of pessimism: The hopelessness scale. J Consult Clin Psychol 1974;42:861-5.
13. Drake RE, Cotton PG. Depression, hopelessness and suicide in chronic schizophrenia. Br J Psychiatry 1986;148:554-9.
14. Beck AT, Steer RA, Kovacs M, Garrison B. Hopelessness and eventual suicide: A 10-year perspective study of patients hospitalized with suicidal ideation. Am J Psychiatry 1985;142:559-63.
15. Riskind JH, Beck AT, Brown G, Steer RA. Taking the measure of anxiety and depression: Validity of the reconstructed Hamilton Scales. J Nerv Ment Dis 1987;175:474-9.
16. Lamberg L. Psychiatric emergencies call for comprehensive assessment and treatment. JAMA 2002;288:686-7.
17. Sadavoy J, Lazarus LW, Jarvik LF. Grossberg GT (eds). Comprehensive review of geriatric psychiatry (2nd ed). Washington, DC: American Psychiatric Press, 1996.
Cognitive enhancers for dementia: Do they work?
No psychiatrist likes to see the month-by-month deterioration in an Alzheimer’s patient—the losses in cognition, the declining ability to function, the behavioral aberrations that upset family and friends.
The problem will accelerate in the decades ahead as the proportion of elderly in the population increase. More than 4 million people in the United States are afflicted with this disorder. Prevalence rates as high as 10% have been estimated for individuals older than 65. Patients with the disease have estimated direct costs of $20,000 to $61,000 per year if the duration lasts 7 to 8 years.1
Although behavioral and functional deficits account for the high costs associated with Alzheimer’s disease (AD), the disorder is defined by cognitive criteria (Box 1). The majority of medication trials have been aimed at symptomatic treatment. More recently, studies have been designed to prevent or delay the onset of AD. Early on, initial therapies directed toward AD were aimed at reversing the cholinergic deficit (Box 2). Clinical trials utilizing lecithin (25-100 g/d) and choline (<16 g/d) as precursors of acetylcholine did not lead to significant benefit.6 Augmenting central cholinergic levels with acetylcholinesterase (AChE) inhibitors has consistently detected symptomatic improvement.
In recent years, the Food and Drug Administration has approved 4 AChE inhibitors—tacrine, donepezil, rivastigmine, and galantamine—for the treatment of AD. I will discuss only the latter 3, since tacrine, the first to Nshow benefit, has a high rate of adverse effects and is of limited use.7 The AChE inhibitors may improve cognition and behavioral symptoms and delay progression of the illness. They can also have beneficial effects on activities of daily living (ADL) and can reduce costs and improve caregiver burden.8
- The development of multiple cognitive deficits manifested by both:
- Memory impairment (impaired ability to learn new information or to recall previously learned information) and
- One (or more) of the following cognitive disturbances:
- Aphasia (language disturbance)
- Apraxia (impaired ability to carry out motor activities despite intact motor function)
- Agnosia (failure to recognize or identify objects despite intact sensory function)
- Disturbance in executive functioning (i.e., planning, organization, sequencing, abstracting)
- The cognitive deficits in Criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning.
- The course is characterized by gradual onset and continuing cognitive decline.
Source: American Psychatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington DC: American Psychiatric Press., 1994.
The three AChE inhibitors have unique basic properties (Box 3). In order to maximize and prolong positive drug effects, it is important to start early and adjust dosage during the treatment9 (Table 1). Side effects are tolerable; the most common include nausea, vomiting, and diarrhea. Titrating the dosage slowly can reduce these. The cholinergic quality of these medications dictate that they be prescribed with caution in patients with bradycardic arrhythmias such as sick sinus syndrome, asthma, or chronic obstructive pulmonary disease.10
Effects on cognition and global assessments
Numerous efficacy studies examining cognition and global assessments in AD patients have been performed with the AChE inhibitors. Their major therapeutic effect is to maintain cognitive function at a constant level during a 6- to 12-month period of treatment, as compared to placebo. Comparison of clinical effects of all 3 agents demonstrates a similar magnitude of improvement. For some drugs, this may represent an upper limit, whereas for others it may still be possible to further increase the benefit.
The pathophysiologic processes implicated in Alzheimer’s disease (AD)include amyloid precursor protein metabolism, tau phosphorylation, apolipoprotein E, inflammation, oxidative stress, and apoptosis. Neuropathological features include amyloid plaques, neurofibrillary tangles, neuronal and synaptic loss, microgliosis, and astrocytosis. The resulting clinical syndrome of dementia is associated with neurotransmitter deficits and intracortical disconnection.
The central cholinergic neurotransmitter system is impaired in AD. This system is involved in learning and memory. The limbic system and neocortex receive projections from the cholinergic system in the septal nuclei and substantia innominata. This includes the medial septal nucleus, diagonal band, and nucleus basalis.2 Literature on animals has demonstrated that basal forebrain lesions impair learning and memory. Cholinergic agonists can improve this. Furthermore, cholinergic antagonists such as scopolamine and atropine can impair learning and memory in humans and animals.3 In AD, a 58% to 93% reduction in choline acetyltransferase levels (and other cholinergic markers) in the cortex and hippocampus can be observed and this correlates with dementia severity.4 Early AD is characterized by neuronal loss and tangles in the cholinergic nucleus basalis of Meynert.5
Results of 4 double-blind, placebo-controlled clinical trials of donepezil, involving more than 1,900 individuals with mild to moderate AD, have been published recently. In all, significant improvements in cognition were observed consistently for both therapeutic doses of donepezil (5 mg/d and 10 mg/d), relative to placebo. Similar benefits were reported for global functioning.
The long-term clinical efficacy and safety of donepezil versus placebo across 1 year in patients with mild to moderate AD was investigated.14 The Gottfries-Brane-Steen global assessment for rating dementia symptoms demonstrated the benefit of donepezil over placebo at weeks 24, 36, and 52, and at the study end point. Advantages of donepezil were also observed in cognition and ADL.
Donepezil also appears to work for patients with moderate to severe AD. In a recent 24-week study,15 patients receiving donepezil showed benefits on the Clinician’s Interview-Based Impression of Change with Caregiver Input (CIBIC+), compared with placebo, at all visits up to week 24 and at the study’s end point. All other secondary measures showed significant differences between the groups in favor of donepezil at the end of the study. These data suggest that donepezil’s benefits extend into more advanced stages of AD than those previously investigated, with good tolerability.
Clinical trials of rivastigmine (1.5-6 mg twice daily PO) have also demonstrated benefits on cognitive and global measures.16 The efficacy of rivastigmine tartrate (ENA 713) in patients with mild to moderately severe Alzheimer’s disease was evaluated in a 26-week open-label extension of a 26-week, double-blind, placebo-controlled study. By 52 weeks, patients originally treated with rivastigmine 6 to 12 mg/d had significantly better cognitive function than did patients originally treated with placebo.17- 19
Donepezil is a second-generation, piperidine-class, selective and reversible acetylcholinesterase (AChE) inhibitor. It is structurally dissimilar from other established AChE inhibitors.
Experimentally, donepezil inhibits AChE activity in human erythrocytes and increases extracellular acetylcholine levels in the cerebral cortex and the hippocampus of the rat. Pharmacologically, donepezil has a half-life of approximately 70h, lending itself to once-daily administration.11
Rivastigmine (ENA 713, or carbamoylatine) is an AChE inhibitor with brain-region selectivity and a long duration of action. Both preclinical studies and studies in human volunteers have shown that rivastigmine induces substantially greater inhibition of AChE in the central nervous system compartment than it does in the periphery (40% inhibition of central AChE compared with 10% inhibition of plasma butylcholinesterase in healthy volunteers). Rivastigmine also preferentially inhibits the G1 enzymatic form of AChE, which predominates in the brains of patients with Alzheimer’s disease (AD).
Evidence from animal studies also suggests that rivastigmine is a more potent inhibitor of AChE in the cortex and hippocampus, the brain regions most affected by AD. The principal metabolite of rivastigmine has at least 10-fold lower activity against AChE compared with the parent drug.
Rivastigmine is completely metabolized; the major route of elimination of the metabolites is renal. Rivastigmine is inactivated during the process of interacting with and inhibiting AChE, and, in contrast to other AChE inhibitors, the hepatic cytochrome P-450 (CYP-450) system is not involved in the metabolism of rivastigmine.12
Galantamine is an allosterically potentiating ligand that modulates nicotinic cholinergic receptors (nAChR) to increase acetylcholine release as well as acting as an AChE inhibitor. In preclinical experiments, the drug significantly improves learning, reduces AChE levels, and increases nicotinic receptor binding. Action of galantamine is on the most abundant nAChR in the human brain, the alpha4/beta2subtype.13
Clinical trials of galantamine (4-12 mg/bid PO) have demonstrated similar benefits.20 Following a 4-week placebo run-in, patients were randomized to 1 of 4 treatment arms: placebo or galantamine escalated to final maintenance dosages of 8, 16, or 24 mg/d for a 5-month treatment phase. At study’s end, the galantamine-place-bo differences on the cognitive subscale of the AD Assessment Scale were 3.3 points for the 16 mg/d group and 3.6 points for the 24 mg/d group. Treatment discontinuations due to adverse events were low in all galantamine groups (6% to 10%) and comparable with that in the placebo group (7%). The incidence of adverse events in the galantamine groups, notably gastrointestinal symptoms, was low and most adverse events were mild.
Other studies examining galantamine have demonstrated similar clinical benefits.8, 21
When using AChE inhibitors, the slope of cognitive decline is similar in treated and untreated patients after the initial improvement. These drugs essentially do not reverse the disorder’s course but shift upward the curve describing the time course of cognitive decline. This applies also to behavioral and functional benefits. Thus the benefit obtained is symptomatic and not neuroprotective, and is lost after discontinuing the medications.
Effects on functioning and behavior
In a 24-week multinational clinical trial, patients receiving donepezil (10 mg/d) were more able than placebo-treated patients to perform complex daily functioning tasks.22 Similar effects have been observed with rivastigmine and galantamine.16, 20
All 3 AChE inhibitors have demonstrated improvements in the behavioral changes associated with AD. Cummings et al23 tested the hypothesis that behavioral disturbances are reported at significantly lower rates by caregivers of AD patients receiving donepezil, compared with a group of patients not receiving a drug for treatment of dementia. Donepezil patients were described as significantly less likely to be threatening, destroy property, and talk loudly, and significantly fewer were treated with sedatives.
Table 1
COMPARING THEAChE INHIBITORS
| Donepezil | Rivastigmine | Galantamine | |
|---|---|---|---|
| Chemical class | Piperidine | Carbamate | Phenanthrene alkaloid |
| AChE inhibitor | Yes | Yes | Yes |
| BuChE inhibitor | Small | Yes | Small |
| Nicotinic modulation | No | No | Yes |
| Elimination half-life | 50-70 h | 0.6-2 h | 5-7 h |
| Administration | Once daily | Twice daily | Twice daily |
| Starting dosage | 5 mg/d | 1.5 mg bid | 4 mg bid |
| Total recommended dosage | 5-10 mg/d | 6-12 mg/d | 16-24 mg/d |
| Adapted from Conn DK. Cholinesterase inhibitors: Comparing the options for mild-to-moderate dementia. Geriatrics56: 56-57, 2001. | |||
An open-label study by Weiner et al24 examined the effects of donepezil on emotional and behavioral symptoms using the CERAD Behavior Rating Scale for Dementia and its subscales. In a group of 25 AD patients treated with donepezil, scores returned to baseline levels at 12 months. In contrast, the scores of the reference group worsened minimally.
Galantamine has also proved effective in treating behavioral symptoms associated with AD. In the Tariot et al20 study, galantamine at 16 mg/d and 24 mg/d had a significantly better outcome on CIBIC+, ADL, and behavioral symptoms versus placebo.
Rosler et al25 assessed the ability of rivastigmine to improve behavioral symptoms in AD. Using the behavioral component of the CIBIC+, results showed that long-term treatment with rivastigmine could slow the progression of symptoms. Symptoms showing stabilization included aggressiveness, activity disturbances, hallucinations, and paranoid features. The results also suggest that patients treated earlier with rivastigmine may attain a greater benefit than those whose treatment is delayed 6 months.
Rivastigmine also has significant effects on controlling behavioral symptoms in patients with Lewy body dementia.26 A placebo-controlled, double-blind, multicenter study was performed in 120 patients with Lewy body dementia. Individuals were given up to 12 mg/d rivastigmine or placebo for 20 weeks, followed by 3 weeks rest. Assessment by neuropsychiatric inventory was made at baseline, and again at weeks 12, 20, and 23.
Patients taking rivastigmine were significantly less apathetic and anxious than those on placebo, and had fewer delusions and hallucinations. Almost twice as many patients on rivastigmine as on placebo (37, 63% versus 18, 30%) showed at least a 30% improvement from baseline. In a computerized cognitive assessment system and neuropsychological tests, patients were significantly faster and better than those on placebo, particularly when performing tasks with a substantial attentional component.
Cost effectiveness
Numerous studies have demonstrated that AChE inhibitors are cost savers in AD treatment. Fillit et al27 examined the impact of donepezil in a multisite managed care organization for 2 years using claims data for 70 individuals with AD and related dementias. The median per diem medical costs were $1.22 lower post treatment than they were in the pretreatment phase. Moreover, posttreatment costs were reduced in 6 of 7 service settings, with median per diem savings of $0.77 in outpatient care and $0.65 in office visits.
Neumann et al28 utilized cost-effectiveness analysis to predict that for mild AD, donepezil would pay for itself in cost offsets if the drug’s effect exceeds 2 years. Donepezil costs were partially offset by a reduction in the costs of care due to enhanced cognitive functioning and the delay in placing the patient in more costly disease stages and settings.
One study used the disease-progression model to estimate potential per-patient savings resulting from the treatment of AD in Canada.29 Rivastigmine was estimated to delay the transition to more severe stages of AD by up to 188 days for patients with mild AD after 2 years of treatment. For patients with mild-to-moderate and moderate disease, this delay was estimated to be 106 and 44 days, respectively.
The Assessment of Health Economics in Alzheimer’s Disease model uses algorithms to predict the time until patients with AD require full-time care. A study, performed in Canada, compared treatment with galantamine to treatment without pharmacological interventions.30 Galantamine was predicted to reduce the duration of full-time care by almost 10%. Approximately 5.6 patients with mild-to-moderate disease must be placed on treatment to avoid 1 year of full-time care, resulting in savings averaging $528 per patient. For patients with moderate disease, 3.9 patients must be placed on treatment to avoid 1 year of full-time care, with savings predicted at $2,533 per patient.
Caregiving burden
Fillit et al addressed caregiver well-being in a self-administered, nationwide survey of AD caregivers. Caregivers of patients treated with donepezil (n = 274) were compared with caregivers of patients not treated with donepezil (n = 274).31 The Caregiver Burden Scale measured time demands and distress linked to commonly performed caregiving tasks. Donepezil caregivers reported significantly lower scores on difficulty of caregiving. Similar findings have been observed with galantamine.32
Related resources
- Bullock R. New drugs for Alzheimer’s disease and other dementias. Br J Psychiatry. 2002;180(2):135-139.
- Brodaty H, Ames D, et al. Pharmacological treatment of cognitive deficits in Alzheimer’s disease. Med J Aust. 2001;175(6):324-329.
- Ahmed MB. Alzheimer’s disease: recent advances in etiology, diagnosis, and management. Tex Med. 2001;97(12):50-58.
- Frisoni GB. Treatment of Alzheimer’s disease with acetyl-cholinesterase inhibitors: bridging the gap between evidence and practice. J Neurol. 2001;248(7):551-7.
Drug brand names
- Tacrine • Cognex
- Donepezil • Aricept
- Rivastigmine • Exelon
- Galantamine • Reminyl
Disclosure
The author reports that he receives grant/research support from, serves as a consultant to, and is on the speaker’s bureau of Janssen Pharmaceutica and Pfizer Inc., and serves as consultant to and is on the speaker’s bureau of Novartis Pharmaceuticals Corp.
1. Irizarry M, Hyman B. Alzheimer’s disease. In: Principles of neuroepidemiology. Batchelor T, Cudkowicz M, eds. Boston: Butterworth-Heinemann, 2001:69-98.
2. Mesulam MM, Mufson EJ, Levey AI, Warner BH. Cholinergic innervation of cortex by the basal forebrain: Cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. J Comp Neurol. 1983a;214:170-197.
3. Drachman DA, Leavitt J. Human memory and the cholinergic system. A relationship to aging? Arch Neurol. 1974;30:113-121.
4. Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet. 1976;2:1403.-
5. Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR. Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol. 1981;10:122-126.
6. Higgins JPT, Flicker L. Lecithin and cognitive impairment. The Cochrane Database of Systematic Reviews. 2001.;
7. Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. The Tacrine Study Group. JAMA. 1994;271:985-991.
8. Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology. 2000;54:2262-2268.
9. Giacobini E. Cholinesterase inhibitors stabilize Alzheimer’s disease. Methods Find Exp Clin Pharmacol. 2000;22:609-613.
10. Irizarry MC, Hyman BT. Alzhemier Disease Therapeutics. J Neuropathology Exp Neurology. 2001;60:923-928.
11. Wilkinson DG. The pharmacology of donepezil: a new treatment of Alzheimer’s disease. Expert Opin Pharmacother. 1999;1:121-135.
12. Polinsky RJ. Clinical pharmacology of rivastigmine: a new-generation acetyl-cholinesterase inhibitor for the treatment of Alzheimer’s disease. Clin Ther. 1998;20:634-647.
13. Samochocki M, Zerlin M, Jostock R, et al. Galantamine is an allosterically potentiating ligand of the human alpha4/beta2 nAChR. Acta Neurol Scand. 2000(Suppl);;176:68-73.
14. Winblad B, Engedal K, Soininen H, Verhey F, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology. 2001;57:489-495.
15. Feldman H, Gauthier S, Hecker J, et al. Donepezil MSAD Study Investigators Group.A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology. 2001;57:613-620.
16. Farlow M, Anand R, Messina J, Jr, Hartman R, Veach J. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease. Eur Neurol. 2000;44:236-241.
17. Rogers S, Friedhoff L. Donepezil Study Group.The efficacy and safety of donepezil in patients with Alzhemier’s disease. Dementia. 1996;7:293-303.
18. Rogers S, Farlow M, Doody R, Morris R, Friedhoff L. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology. 1998;50:136-145.
19. Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, DalBianco P, Stahelin HB, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: International randomized controlled trial. BMJ. 1999;318:633-638.
20. Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology. 2000;54:2269-2276.
21. Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: Multicentre randomized controlled trial. Galantamine International - 1 Study Group. BMJ. 2000;321:1445-1449.
22. Knopman DS. Management of cognition and function: new results from the clinical trials programme of Aricept (R) (donepezil Hcl). Int J Neuropsychopharmacol. 2000;3:13-20.
23. Cummings JL, Donohue JA, Brooks RL. The relationship between donepezil and behavioral disturbances in patients with Alzheimer’s disease. Am J Geriatr Psychiatry. 2000;8:134-140.
24. Weiner MF, Martin-Cook K, Foster BM, Saine K, et al. Effects of donepezil on emotional/behavioral symptoms in Alzheimer’s disease patients. J Clin Psychiatry. 2000;487-492.
25. Rosler M, Retz W, Retz-Junginger P, Dennler HJ. Effects of two-year treatment with the cholinesterase inhibitor rivastigmine on behavioural symptoms in Alzheimer’s disease. Behav Neurol. 1998;11:211-216.
26. McKeith I, Del Ser T, Spano P, Emre M, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet. 2000;356(9247):2031-2036.
27. Fillit H, Gutterman EM, Lewis B. Donepezil use in managed Medicare: effect on health care costs and utilization. Clin Ther. 1999;21:2173-2185.
28. Neumann PJ, Hermann RC, Kuntz KM, Araki SS, Duff SB, Leon J, Berenbaum PA, et al. Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer’s disease. Neurology. 1999;52:1115-1116.
29. Hauber AB, Gnanasakthy A, Mauskopf JA. Savings in the cost of caring for patients with Alzheimer’s disease in Canada: an analysis of treatment with rivastigmine. Clin Ther. 2000;22:439-451.
30. Getsios D, Caro JJ, Caro G, Ishak K. The AHEAD Study Group. Assessment of health economics in Alzheimer’s disease (AHEAD): galantamine treatment in Canada. Neurology. 2001;57:972-978.
31. Fillit HM, Gutterman EM, Brooks RL. Impact of donepezil on caregiving burden for patients with Alzheimer’s disease. Int Psychogeriatr. 2000;12(3):389-401.
32. Blesa R. Galantamine: therapeutic effects beyond cognition. Dement Geriatr Cogn Disord. 2000;11(Suppl)1:28-34.
No psychiatrist likes to see the month-by-month deterioration in an Alzheimer’s patient—the losses in cognition, the declining ability to function, the behavioral aberrations that upset family and friends.
The problem will accelerate in the decades ahead as the proportion of elderly in the population increase. More than 4 million people in the United States are afflicted with this disorder. Prevalence rates as high as 10% have been estimated for individuals older than 65. Patients with the disease have estimated direct costs of $20,000 to $61,000 per year if the duration lasts 7 to 8 years.1
Although behavioral and functional deficits account for the high costs associated with Alzheimer’s disease (AD), the disorder is defined by cognitive criteria (Box 1). The majority of medication trials have been aimed at symptomatic treatment. More recently, studies have been designed to prevent or delay the onset of AD. Early on, initial therapies directed toward AD were aimed at reversing the cholinergic deficit (Box 2). Clinical trials utilizing lecithin (25-100 g/d) and choline (<16 g/d) as precursors of acetylcholine did not lead to significant benefit.6 Augmenting central cholinergic levels with acetylcholinesterase (AChE) inhibitors has consistently detected symptomatic improvement.
In recent years, the Food and Drug Administration has approved 4 AChE inhibitors—tacrine, donepezil, rivastigmine, and galantamine—for the treatment of AD. I will discuss only the latter 3, since tacrine, the first to Nshow benefit, has a high rate of adverse effects and is of limited use.7 The AChE inhibitors may improve cognition and behavioral symptoms and delay progression of the illness. They can also have beneficial effects on activities of daily living (ADL) and can reduce costs and improve caregiver burden.8
- The development of multiple cognitive deficits manifested by both:
- Memory impairment (impaired ability to learn new information or to recall previously learned information) and
- One (or more) of the following cognitive disturbances:
- Aphasia (language disturbance)
- Apraxia (impaired ability to carry out motor activities despite intact motor function)
- Agnosia (failure to recognize or identify objects despite intact sensory function)
- Disturbance in executive functioning (i.e., planning, organization, sequencing, abstracting)
- The cognitive deficits in Criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning.
- The course is characterized by gradual onset and continuing cognitive decline.
Source: American Psychatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington DC: American Psychiatric Press., 1994.
The three AChE inhibitors have unique basic properties (Box 3). In order to maximize and prolong positive drug effects, it is important to start early and adjust dosage during the treatment9 (Table 1). Side effects are tolerable; the most common include nausea, vomiting, and diarrhea. Titrating the dosage slowly can reduce these. The cholinergic quality of these medications dictate that they be prescribed with caution in patients with bradycardic arrhythmias such as sick sinus syndrome, asthma, or chronic obstructive pulmonary disease.10
Effects on cognition and global assessments
Numerous efficacy studies examining cognition and global assessments in AD patients have been performed with the AChE inhibitors. Their major therapeutic effect is to maintain cognitive function at a constant level during a 6- to 12-month period of treatment, as compared to placebo. Comparison of clinical effects of all 3 agents demonstrates a similar magnitude of improvement. For some drugs, this may represent an upper limit, whereas for others it may still be possible to further increase the benefit.
The pathophysiologic processes implicated in Alzheimer’s disease (AD)include amyloid precursor protein metabolism, tau phosphorylation, apolipoprotein E, inflammation, oxidative stress, and apoptosis. Neuropathological features include amyloid plaques, neurofibrillary tangles, neuronal and synaptic loss, microgliosis, and astrocytosis. The resulting clinical syndrome of dementia is associated with neurotransmitter deficits and intracortical disconnection.
The central cholinergic neurotransmitter system is impaired in AD. This system is involved in learning and memory. The limbic system and neocortex receive projections from the cholinergic system in the septal nuclei and substantia innominata. This includes the medial septal nucleus, diagonal band, and nucleus basalis.2 Literature on animals has demonstrated that basal forebrain lesions impair learning and memory. Cholinergic agonists can improve this. Furthermore, cholinergic antagonists such as scopolamine and atropine can impair learning and memory in humans and animals.3 In AD, a 58% to 93% reduction in choline acetyltransferase levels (and other cholinergic markers) in the cortex and hippocampus can be observed and this correlates with dementia severity.4 Early AD is characterized by neuronal loss and tangles in the cholinergic nucleus basalis of Meynert.5
Results of 4 double-blind, placebo-controlled clinical trials of donepezil, involving more than 1,900 individuals with mild to moderate AD, have been published recently. In all, significant improvements in cognition were observed consistently for both therapeutic doses of donepezil (5 mg/d and 10 mg/d), relative to placebo. Similar benefits were reported for global functioning.
The long-term clinical efficacy and safety of donepezil versus placebo across 1 year in patients with mild to moderate AD was investigated.14 The Gottfries-Brane-Steen global assessment for rating dementia symptoms demonstrated the benefit of donepezil over placebo at weeks 24, 36, and 52, and at the study end point. Advantages of donepezil were also observed in cognition and ADL.
Donepezil also appears to work for patients with moderate to severe AD. In a recent 24-week study,15 patients receiving donepezil showed benefits on the Clinician’s Interview-Based Impression of Change with Caregiver Input (CIBIC+), compared with placebo, at all visits up to week 24 and at the study’s end point. All other secondary measures showed significant differences between the groups in favor of donepezil at the end of the study. These data suggest that donepezil’s benefits extend into more advanced stages of AD than those previously investigated, with good tolerability.
Clinical trials of rivastigmine (1.5-6 mg twice daily PO) have also demonstrated benefits on cognitive and global measures.16 The efficacy of rivastigmine tartrate (ENA 713) in patients with mild to moderately severe Alzheimer’s disease was evaluated in a 26-week open-label extension of a 26-week, double-blind, placebo-controlled study. By 52 weeks, patients originally treated with rivastigmine 6 to 12 mg/d had significantly better cognitive function than did patients originally treated with placebo.17- 19
Donepezil is a second-generation, piperidine-class, selective and reversible acetylcholinesterase (AChE) inhibitor. It is structurally dissimilar from other established AChE inhibitors.
Experimentally, donepezil inhibits AChE activity in human erythrocytes and increases extracellular acetylcholine levels in the cerebral cortex and the hippocampus of the rat. Pharmacologically, donepezil has a half-life of approximately 70h, lending itself to once-daily administration.11
Rivastigmine (ENA 713, or carbamoylatine) is an AChE inhibitor with brain-region selectivity and a long duration of action. Both preclinical studies and studies in human volunteers have shown that rivastigmine induces substantially greater inhibition of AChE in the central nervous system compartment than it does in the periphery (40% inhibition of central AChE compared with 10% inhibition of plasma butylcholinesterase in healthy volunteers). Rivastigmine also preferentially inhibits the G1 enzymatic form of AChE, which predominates in the brains of patients with Alzheimer’s disease (AD).
Evidence from animal studies also suggests that rivastigmine is a more potent inhibitor of AChE in the cortex and hippocampus, the brain regions most affected by AD. The principal metabolite of rivastigmine has at least 10-fold lower activity against AChE compared with the parent drug.
Rivastigmine is completely metabolized; the major route of elimination of the metabolites is renal. Rivastigmine is inactivated during the process of interacting with and inhibiting AChE, and, in contrast to other AChE inhibitors, the hepatic cytochrome P-450 (CYP-450) system is not involved in the metabolism of rivastigmine.12
Galantamine is an allosterically potentiating ligand that modulates nicotinic cholinergic receptors (nAChR) to increase acetylcholine release as well as acting as an AChE inhibitor. In preclinical experiments, the drug significantly improves learning, reduces AChE levels, and increases nicotinic receptor binding. Action of galantamine is on the most abundant nAChR in the human brain, the alpha4/beta2subtype.13
Clinical trials of galantamine (4-12 mg/bid PO) have demonstrated similar benefits.20 Following a 4-week placebo run-in, patients were randomized to 1 of 4 treatment arms: placebo or galantamine escalated to final maintenance dosages of 8, 16, or 24 mg/d for a 5-month treatment phase. At study’s end, the galantamine-place-bo differences on the cognitive subscale of the AD Assessment Scale were 3.3 points for the 16 mg/d group and 3.6 points for the 24 mg/d group. Treatment discontinuations due to adverse events were low in all galantamine groups (6% to 10%) and comparable with that in the placebo group (7%). The incidence of adverse events in the galantamine groups, notably gastrointestinal symptoms, was low and most adverse events were mild.
Other studies examining galantamine have demonstrated similar clinical benefits.8, 21
When using AChE inhibitors, the slope of cognitive decline is similar in treated and untreated patients after the initial improvement. These drugs essentially do not reverse the disorder’s course but shift upward the curve describing the time course of cognitive decline. This applies also to behavioral and functional benefits. Thus the benefit obtained is symptomatic and not neuroprotective, and is lost after discontinuing the medications.
Effects on functioning and behavior
In a 24-week multinational clinical trial, patients receiving donepezil (10 mg/d) were more able than placebo-treated patients to perform complex daily functioning tasks.22 Similar effects have been observed with rivastigmine and galantamine.16, 20
All 3 AChE inhibitors have demonstrated improvements in the behavioral changes associated with AD. Cummings et al23 tested the hypothesis that behavioral disturbances are reported at significantly lower rates by caregivers of AD patients receiving donepezil, compared with a group of patients not receiving a drug for treatment of dementia. Donepezil patients were described as significantly less likely to be threatening, destroy property, and talk loudly, and significantly fewer were treated with sedatives.
Table 1
COMPARING THEAChE INHIBITORS
| Donepezil | Rivastigmine | Galantamine | |
|---|---|---|---|
| Chemical class | Piperidine | Carbamate | Phenanthrene alkaloid |
| AChE inhibitor | Yes | Yes | Yes |
| BuChE inhibitor | Small | Yes | Small |
| Nicotinic modulation | No | No | Yes |
| Elimination half-life | 50-70 h | 0.6-2 h | 5-7 h |
| Administration | Once daily | Twice daily | Twice daily |
| Starting dosage | 5 mg/d | 1.5 mg bid | 4 mg bid |
| Total recommended dosage | 5-10 mg/d | 6-12 mg/d | 16-24 mg/d |
| Adapted from Conn DK. Cholinesterase inhibitors: Comparing the options for mild-to-moderate dementia. Geriatrics56: 56-57, 2001. | |||
An open-label study by Weiner et al24 examined the effects of donepezil on emotional and behavioral symptoms using the CERAD Behavior Rating Scale for Dementia and its subscales. In a group of 25 AD patients treated with donepezil, scores returned to baseline levels at 12 months. In contrast, the scores of the reference group worsened minimally.
Galantamine has also proved effective in treating behavioral symptoms associated with AD. In the Tariot et al20 study, galantamine at 16 mg/d and 24 mg/d had a significantly better outcome on CIBIC+, ADL, and behavioral symptoms versus placebo.
Rosler et al25 assessed the ability of rivastigmine to improve behavioral symptoms in AD. Using the behavioral component of the CIBIC+, results showed that long-term treatment with rivastigmine could slow the progression of symptoms. Symptoms showing stabilization included aggressiveness, activity disturbances, hallucinations, and paranoid features. The results also suggest that patients treated earlier with rivastigmine may attain a greater benefit than those whose treatment is delayed 6 months.
Rivastigmine also has significant effects on controlling behavioral symptoms in patients with Lewy body dementia.26 A placebo-controlled, double-blind, multicenter study was performed in 120 patients with Lewy body dementia. Individuals were given up to 12 mg/d rivastigmine or placebo for 20 weeks, followed by 3 weeks rest. Assessment by neuropsychiatric inventory was made at baseline, and again at weeks 12, 20, and 23.
Patients taking rivastigmine were significantly less apathetic and anxious than those on placebo, and had fewer delusions and hallucinations. Almost twice as many patients on rivastigmine as on placebo (37, 63% versus 18, 30%) showed at least a 30% improvement from baseline. In a computerized cognitive assessment system and neuropsychological tests, patients were significantly faster and better than those on placebo, particularly when performing tasks with a substantial attentional component.
Cost effectiveness
Numerous studies have demonstrated that AChE inhibitors are cost savers in AD treatment. Fillit et al27 examined the impact of donepezil in a multisite managed care organization for 2 years using claims data for 70 individuals with AD and related dementias. The median per diem medical costs were $1.22 lower post treatment than they were in the pretreatment phase. Moreover, posttreatment costs were reduced in 6 of 7 service settings, with median per diem savings of $0.77 in outpatient care and $0.65 in office visits.
Neumann et al28 utilized cost-effectiveness analysis to predict that for mild AD, donepezil would pay for itself in cost offsets if the drug’s effect exceeds 2 years. Donepezil costs were partially offset by a reduction in the costs of care due to enhanced cognitive functioning and the delay in placing the patient in more costly disease stages and settings.
One study used the disease-progression model to estimate potential per-patient savings resulting from the treatment of AD in Canada.29 Rivastigmine was estimated to delay the transition to more severe stages of AD by up to 188 days for patients with mild AD after 2 years of treatment. For patients with mild-to-moderate and moderate disease, this delay was estimated to be 106 and 44 days, respectively.
The Assessment of Health Economics in Alzheimer’s Disease model uses algorithms to predict the time until patients with AD require full-time care. A study, performed in Canada, compared treatment with galantamine to treatment without pharmacological interventions.30 Galantamine was predicted to reduce the duration of full-time care by almost 10%. Approximately 5.6 patients with mild-to-moderate disease must be placed on treatment to avoid 1 year of full-time care, resulting in savings averaging $528 per patient. For patients with moderate disease, 3.9 patients must be placed on treatment to avoid 1 year of full-time care, with savings predicted at $2,533 per patient.
Caregiving burden
Fillit et al addressed caregiver well-being in a self-administered, nationwide survey of AD caregivers. Caregivers of patients treated with donepezil (n = 274) were compared with caregivers of patients not treated with donepezil (n = 274).31 The Caregiver Burden Scale measured time demands and distress linked to commonly performed caregiving tasks. Donepezil caregivers reported significantly lower scores on difficulty of caregiving. Similar findings have been observed with galantamine.32
Related resources
- Bullock R. New drugs for Alzheimer’s disease and other dementias. Br J Psychiatry. 2002;180(2):135-139.
- Brodaty H, Ames D, et al. Pharmacological treatment of cognitive deficits in Alzheimer’s disease. Med J Aust. 2001;175(6):324-329.
- Ahmed MB. Alzheimer’s disease: recent advances in etiology, diagnosis, and management. Tex Med. 2001;97(12):50-58.
- Frisoni GB. Treatment of Alzheimer’s disease with acetyl-cholinesterase inhibitors: bridging the gap between evidence and practice. J Neurol. 2001;248(7):551-7.
Drug brand names
- Tacrine • Cognex
- Donepezil • Aricept
- Rivastigmine • Exelon
- Galantamine • Reminyl
Disclosure
The author reports that he receives grant/research support from, serves as a consultant to, and is on the speaker’s bureau of Janssen Pharmaceutica and Pfizer Inc., and serves as consultant to and is on the speaker’s bureau of Novartis Pharmaceuticals Corp.
No psychiatrist likes to see the month-by-month deterioration in an Alzheimer’s patient—the losses in cognition, the declining ability to function, the behavioral aberrations that upset family and friends.
The problem will accelerate in the decades ahead as the proportion of elderly in the population increase. More than 4 million people in the United States are afflicted with this disorder. Prevalence rates as high as 10% have been estimated for individuals older than 65. Patients with the disease have estimated direct costs of $20,000 to $61,000 per year if the duration lasts 7 to 8 years.1
Although behavioral and functional deficits account for the high costs associated with Alzheimer’s disease (AD), the disorder is defined by cognitive criteria (Box 1). The majority of medication trials have been aimed at symptomatic treatment. More recently, studies have been designed to prevent or delay the onset of AD. Early on, initial therapies directed toward AD were aimed at reversing the cholinergic deficit (Box 2). Clinical trials utilizing lecithin (25-100 g/d) and choline (<16 g/d) as precursors of acetylcholine did not lead to significant benefit.6 Augmenting central cholinergic levels with acetylcholinesterase (AChE) inhibitors has consistently detected symptomatic improvement.
In recent years, the Food and Drug Administration has approved 4 AChE inhibitors—tacrine, donepezil, rivastigmine, and galantamine—for the treatment of AD. I will discuss only the latter 3, since tacrine, the first to Nshow benefit, has a high rate of adverse effects and is of limited use.7 The AChE inhibitors may improve cognition and behavioral symptoms and delay progression of the illness. They can also have beneficial effects on activities of daily living (ADL) and can reduce costs and improve caregiver burden.8
- The development of multiple cognitive deficits manifested by both:
- Memory impairment (impaired ability to learn new information or to recall previously learned information) and
- One (or more) of the following cognitive disturbances:
- Aphasia (language disturbance)
- Apraxia (impaired ability to carry out motor activities despite intact motor function)
- Agnosia (failure to recognize or identify objects despite intact sensory function)
- Disturbance in executive functioning (i.e., planning, organization, sequencing, abstracting)
- The cognitive deficits in Criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning.
- The course is characterized by gradual onset and continuing cognitive decline.
Source: American Psychatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington DC: American Psychiatric Press., 1994.
The three AChE inhibitors have unique basic properties (Box 3). In order to maximize and prolong positive drug effects, it is important to start early and adjust dosage during the treatment9 (Table 1). Side effects are tolerable; the most common include nausea, vomiting, and diarrhea. Titrating the dosage slowly can reduce these. The cholinergic quality of these medications dictate that they be prescribed with caution in patients with bradycardic arrhythmias such as sick sinus syndrome, asthma, or chronic obstructive pulmonary disease.10
Effects on cognition and global assessments
Numerous efficacy studies examining cognition and global assessments in AD patients have been performed with the AChE inhibitors. Their major therapeutic effect is to maintain cognitive function at a constant level during a 6- to 12-month period of treatment, as compared to placebo. Comparison of clinical effects of all 3 agents demonstrates a similar magnitude of improvement. For some drugs, this may represent an upper limit, whereas for others it may still be possible to further increase the benefit.
The pathophysiologic processes implicated in Alzheimer’s disease (AD)include amyloid precursor protein metabolism, tau phosphorylation, apolipoprotein E, inflammation, oxidative stress, and apoptosis. Neuropathological features include amyloid plaques, neurofibrillary tangles, neuronal and synaptic loss, microgliosis, and astrocytosis. The resulting clinical syndrome of dementia is associated with neurotransmitter deficits and intracortical disconnection.
The central cholinergic neurotransmitter system is impaired in AD. This system is involved in learning and memory. The limbic system and neocortex receive projections from the cholinergic system in the septal nuclei and substantia innominata. This includes the medial septal nucleus, diagonal band, and nucleus basalis.2 Literature on animals has demonstrated that basal forebrain lesions impair learning and memory. Cholinergic agonists can improve this. Furthermore, cholinergic antagonists such as scopolamine and atropine can impair learning and memory in humans and animals.3 In AD, a 58% to 93% reduction in choline acetyltransferase levels (and other cholinergic markers) in the cortex and hippocampus can be observed and this correlates with dementia severity.4 Early AD is characterized by neuronal loss and tangles in the cholinergic nucleus basalis of Meynert.5
Results of 4 double-blind, placebo-controlled clinical trials of donepezil, involving more than 1,900 individuals with mild to moderate AD, have been published recently. In all, significant improvements in cognition were observed consistently for both therapeutic doses of donepezil (5 mg/d and 10 mg/d), relative to placebo. Similar benefits were reported for global functioning.
The long-term clinical efficacy and safety of donepezil versus placebo across 1 year in patients with mild to moderate AD was investigated.14 The Gottfries-Brane-Steen global assessment for rating dementia symptoms demonstrated the benefit of donepezil over placebo at weeks 24, 36, and 52, and at the study end point. Advantages of donepezil were also observed in cognition and ADL.
Donepezil also appears to work for patients with moderate to severe AD. In a recent 24-week study,15 patients receiving donepezil showed benefits on the Clinician’s Interview-Based Impression of Change with Caregiver Input (CIBIC+), compared with placebo, at all visits up to week 24 and at the study’s end point. All other secondary measures showed significant differences between the groups in favor of donepezil at the end of the study. These data suggest that donepezil’s benefits extend into more advanced stages of AD than those previously investigated, with good tolerability.
Clinical trials of rivastigmine (1.5-6 mg twice daily PO) have also demonstrated benefits on cognitive and global measures.16 The efficacy of rivastigmine tartrate (ENA 713) in patients with mild to moderately severe Alzheimer’s disease was evaluated in a 26-week open-label extension of a 26-week, double-blind, placebo-controlled study. By 52 weeks, patients originally treated with rivastigmine 6 to 12 mg/d had significantly better cognitive function than did patients originally treated with placebo.17- 19
Donepezil is a second-generation, piperidine-class, selective and reversible acetylcholinesterase (AChE) inhibitor. It is structurally dissimilar from other established AChE inhibitors.
Experimentally, donepezil inhibits AChE activity in human erythrocytes and increases extracellular acetylcholine levels in the cerebral cortex and the hippocampus of the rat. Pharmacologically, donepezil has a half-life of approximately 70h, lending itself to once-daily administration.11
Rivastigmine (ENA 713, or carbamoylatine) is an AChE inhibitor with brain-region selectivity and a long duration of action. Both preclinical studies and studies in human volunteers have shown that rivastigmine induces substantially greater inhibition of AChE in the central nervous system compartment than it does in the periphery (40% inhibition of central AChE compared with 10% inhibition of plasma butylcholinesterase in healthy volunteers). Rivastigmine also preferentially inhibits the G1 enzymatic form of AChE, which predominates in the brains of patients with Alzheimer’s disease (AD).
Evidence from animal studies also suggests that rivastigmine is a more potent inhibitor of AChE in the cortex and hippocampus, the brain regions most affected by AD. The principal metabolite of rivastigmine has at least 10-fold lower activity against AChE compared with the parent drug.
Rivastigmine is completely metabolized; the major route of elimination of the metabolites is renal. Rivastigmine is inactivated during the process of interacting with and inhibiting AChE, and, in contrast to other AChE inhibitors, the hepatic cytochrome P-450 (CYP-450) system is not involved in the metabolism of rivastigmine.12
Galantamine is an allosterically potentiating ligand that modulates nicotinic cholinergic receptors (nAChR) to increase acetylcholine release as well as acting as an AChE inhibitor. In preclinical experiments, the drug significantly improves learning, reduces AChE levels, and increases nicotinic receptor binding. Action of galantamine is on the most abundant nAChR in the human brain, the alpha4/beta2subtype.13
Clinical trials of galantamine (4-12 mg/bid PO) have demonstrated similar benefits.20 Following a 4-week placebo run-in, patients were randomized to 1 of 4 treatment arms: placebo or galantamine escalated to final maintenance dosages of 8, 16, or 24 mg/d for a 5-month treatment phase. At study’s end, the galantamine-place-bo differences on the cognitive subscale of the AD Assessment Scale were 3.3 points for the 16 mg/d group and 3.6 points for the 24 mg/d group. Treatment discontinuations due to adverse events were low in all galantamine groups (6% to 10%) and comparable with that in the placebo group (7%). The incidence of adverse events in the galantamine groups, notably gastrointestinal symptoms, was low and most adverse events were mild.
Other studies examining galantamine have demonstrated similar clinical benefits.8, 21
When using AChE inhibitors, the slope of cognitive decline is similar in treated and untreated patients after the initial improvement. These drugs essentially do not reverse the disorder’s course but shift upward the curve describing the time course of cognitive decline. This applies also to behavioral and functional benefits. Thus the benefit obtained is symptomatic and not neuroprotective, and is lost after discontinuing the medications.
Effects on functioning and behavior
In a 24-week multinational clinical trial, patients receiving donepezil (10 mg/d) were more able than placebo-treated patients to perform complex daily functioning tasks.22 Similar effects have been observed with rivastigmine and galantamine.16, 20
All 3 AChE inhibitors have demonstrated improvements in the behavioral changes associated with AD. Cummings et al23 tested the hypothesis that behavioral disturbances are reported at significantly lower rates by caregivers of AD patients receiving donepezil, compared with a group of patients not receiving a drug for treatment of dementia. Donepezil patients were described as significantly less likely to be threatening, destroy property, and talk loudly, and significantly fewer were treated with sedatives.
Table 1
COMPARING THEAChE INHIBITORS
| Donepezil | Rivastigmine | Galantamine | |
|---|---|---|---|
| Chemical class | Piperidine | Carbamate | Phenanthrene alkaloid |
| AChE inhibitor | Yes | Yes | Yes |
| BuChE inhibitor | Small | Yes | Small |
| Nicotinic modulation | No | No | Yes |
| Elimination half-life | 50-70 h | 0.6-2 h | 5-7 h |
| Administration | Once daily | Twice daily | Twice daily |
| Starting dosage | 5 mg/d | 1.5 mg bid | 4 mg bid |
| Total recommended dosage | 5-10 mg/d | 6-12 mg/d | 16-24 mg/d |
| Adapted from Conn DK. Cholinesterase inhibitors: Comparing the options for mild-to-moderate dementia. Geriatrics56: 56-57, 2001. | |||
An open-label study by Weiner et al24 examined the effects of donepezil on emotional and behavioral symptoms using the CERAD Behavior Rating Scale for Dementia and its subscales. In a group of 25 AD patients treated with donepezil, scores returned to baseline levels at 12 months. In contrast, the scores of the reference group worsened minimally.
Galantamine has also proved effective in treating behavioral symptoms associated with AD. In the Tariot et al20 study, galantamine at 16 mg/d and 24 mg/d had a significantly better outcome on CIBIC+, ADL, and behavioral symptoms versus placebo.
Rosler et al25 assessed the ability of rivastigmine to improve behavioral symptoms in AD. Using the behavioral component of the CIBIC+, results showed that long-term treatment with rivastigmine could slow the progression of symptoms. Symptoms showing stabilization included aggressiveness, activity disturbances, hallucinations, and paranoid features. The results also suggest that patients treated earlier with rivastigmine may attain a greater benefit than those whose treatment is delayed 6 months.
Rivastigmine also has significant effects on controlling behavioral symptoms in patients with Lewy body dementia.26 A placebo-controlled, double-blind, multicenter study was performed in 120 patients with Lewy body dementia. Individuals were given up to 12 mg/d rivastigmine or placebo for 20 weeks, followed by 3 weeks rest. Assessment by neuropsychiatric inventory was made at baseline, and again at weeks 12, 20, and 23.
Patients taking rivastigmine were significantly less apathetic and anxious than those on placebo, and had fewer delusions and hallucinations. Almost twice as many patients on rivastigmine as on placebo (37, 63% versus 18, 30%) showed at least a 30% improvement from baseline. In a computerized cognitive assessment system and neuropsychological tests, patients were significantly faster and better than those on placebo, particularly when performing tasks with a substantial attentional component.
Cost effectiveness
Numerous studies have demonstrated that AChE inhibitors are cost savers in AD treatment. Fillit et al27 examined the impact of donepezil in a multisite managed care organization for 2 years using claims data for 70 individuals with AD and related dementias. The median per diem medical costs were $1.22 lower post treatment than they were in the pretreatment phase. Moreover, posttreatment costs were reduced in 6 of 7 service settings, with median per diem savings of $0.77 in outpatient care and $0.65 in office visits.
Neumann et al28 utilized cost-effectiveness analysis to predict that for mild AD, donepezil would pay for itself in cost offsets if the drug’s effect exceeds 2 years. Donepezil costs were partially offset by a reduction in the costs of care due to enhanced cognitive functioning and the delay in placing the patient in more costly disease stages and settings.
One study used the disease-progression model to estimate potential per-patient savings resulting from the treatment of AD in Canada.29 Rivastigmine was estimated to delay the transition to more severe stages of AD by up to 188 days for patients with mild AD after 2 years of treatment. For patients with mild-to-moderate and moderate disease, this delay was estimated to be 106 and 44 days, respectively.
The Assessment of Health Economics in Alzheimer’s Disease model uses algorithms to predict the time until patients with AD require full-time care. A study, performed in Canada, compared treatment with galantamine to treatment without pharmacological interventions.30 Galantamine was predicted to reduce the duration of full-time care by almost 10%. Approximately 5.6 patients with mild-to-moderate disease must be placed on treatment to avoid 1 year of full-time care, resulting in savings averaging $528 per patient. For patients with moderate disease, 3.9 patients must be placed on treatment to avoid 1 year of full-time care, with savings predicted at $2,533 per patient.
Caregiving burden
Fillit et al addressed caregiver well-being in a self-administered, nationwide survey of AD caregivers. Caregivers of patients treated with donepezil (n = 274) were compared with caregivers of patients not treated with donepezil (n = 274).31 The Caregiver Burden Scale measured time demands and distress linked to commonly performed caregiving tasks. Donepezil caregivers reported significantly lower scores on difficulty of caregiving. Similar findings have been observed with galantamine.32
Related resources
- Bullock R. New drugs for Alzheimer’s disease and other dementias. Br J Psychiatry. 2002;180(2):135-139.
- Brodaty H, Ames D, et al. Pharmacological treatment of cognitive deficits in Alzheimer’s disease. Med J Aust. 2001;175(6):324-329.
- Ahmed MB. Alzheimer’s disease: recent advances in etiology, diagnosis, and management. Tex Med. 2001;97(12):50-58.
- Frisoni GB. Treatment of Alzheimer’s disease with acetyl-cholinesterase inhibitors: bridging the gap between evidence and practice. J Neurol. 2001;248(7):551-7.
Drug brand names
- Tacrine • Cognex
- Donepezil • Aricept
- Rivastigmine • Exelon
- Galantamine • Reminyl
Disclosure
The author reports that he receives grant/research support from, serves as a consultant to, and is on the speaker’s bureau of Janssen Pharmaceutica and Pfizer Inc., and serves as consultant to and is on the speaker’s bureau of Novartis Pharmaceuticals Corp.
1. Irizarry M, Hyman B. Alzheimer’s disease. In: Principles of neuroepidemiology. Batchelor T, Cudkowicz M, eds. Boston: Butterworth-Heinemann, 2001:69-98.
2. Mesulam MM, Mufson EJ, Levey AI, Warner BH. Cholinergic innervation of cortex by the basal forebrain: Cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. J Comp Neurol. 1983a;214:170-197.
3. Drachman DA, Leavitt J. Human memory and the cholinergic system. A relationship to aging? Arch Neurol. 1974;30:113-121.
4. Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet. 1976;2:1403.-
5. Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR. Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol. 1981;10:122-126.
6. Higgins JPT, Flicker L. Lecithin and cognitive impairment. The Cochrane Database of Systematic Reviews. 2001.;
7. Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. The Tacrine Study Group. JAMA. 1994;271:985-991.
8. Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology. 2000;54:2262-2268.
9. Giacobini E. Cholinesterase inhibitors stabilize Alzheimer’s disease. Methods Find Exp Clin Pharmacol. 2000;22:609-613.
10. Irizarry MC, Hyman BT. Alzhemier Disease Therapeutics. J Neuropathology Exp Neurology. 2001;60:923-928.
11. Wilkinson DG. The pharmacology of donepezil: a new treatment of Alzheimer’s disease. Expert Opin Pharmacother. 1999;1:121-135.
12. Polinsky RJ. Clinical pharmacology of rivastigmine: a new-generation acetyl-cholinesterase inhibitor for the treatment of Alzheimer’s disease. Clin Ther. 1998;20:634-647.
13. Samochocki M, Zerlin M, Jostock R, et al. Galantamine is an allosterically potentiating ligand of the human alpha4/beta2 nAChR. Acta Neurol Scand. 2000(Suppl);;176:68-73.
14. Winblad B, Engedal K, Soininen H, Verhey F, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology. 2001;57:489-495.
15. Feldman H, Gauthier S, Hecker J, et al. Donepezil MSAD Study Investigators Group.A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology. 2001;57:613-620.
16. Farlow M, Anand R, Messina J, Jr, Hartman R, Veach J. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease. Eur Neurol. 2000;44:236-241.
17. Rogers S, Friedhoff L. Donepezil Study Group.The efficacy and safety of donepezil in patients with Alzhemier’s disease. Dementia. 1996;7:293-303.
18. Rogers S, Farlow M, Doody R, Morris R, Friedhoff L. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology. 1998;50:136-145.
19. Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, DalBianco P, Stahelin HB, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: International randomized controlled trial. BMJ. 1999;318:633-638.
20. Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology. 2000;54:2269-2276.
21. Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: Multicentre randomized controlled trial. Galantamine International - 1 Study Group. BMJ. 2000;321:1445-1449.
22. Knopman DS. Management of cognition and function: new results from the clinical trials programme of Aricept (R) (donepezil Hcl). Int J Neuropsychopharmacol. 2000;3:13-20.
23. Cummings JL, Donohue JA, Brooks RL. The relationship between donepezil and behavioral disturbances in patients with Alzheimer’s disease. Am J Geriatr Psychiatry. 2000;8:134-140.
24. Weiner MF, Martin-Cook K, Foster BM, Saine K, et al. Effects of donepezil on emotional/behavioral symptoms in Alzheimer’s disease patients. J Clin Psychiatry. 2000;487-492.
25. Rosler M, Retz W, Retz-Junginger P, Dennler HJ. Effects of two-year treatment with the cholinesterase inhibitor rivastigmine on behavioural symptoms in Alzheimer’s disease. Behav Neurol. 1998;11:211-216.
26. McKeith I, Del Ser T, Spano P, Emre M, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet. 2000;356(9247):2031-2036.
27. Fillit H, Gutterman EM, Lewis B. Donepezil use in managed Medicare: effect on health care costs and utilization. Clin Ther. 1999;21:2173-2185.
28. Neumann PJ, Hermann RC, Kuntz KM, Araki SS, Duff SB, Leon J, Berenbaum PA, et al. Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer’s disease. Neurology. 1999;52:1115-1116.
29. Hauber AB, Gnanasakthy A, Mauskopf JA. Savings in the cost of caring for patients with Alzheimer’s disease in Canada: an analysis of treatment with rivastigmine. Clin Ther. 2000;22:439-451.
30. Getsios D, Caro JJ, Caro G, Ishak K. The AHEAD Study Group. Assessment of health economics in Alzheimer’s disease (AHEAD): galantamine treatment in Canada. Neurology. 2001;57:972-978.
31. Fillit HM, Gutterman EM, Brooks RL. Impact of donepezil on caregiving burden for patients with Alzheimer’s disease. Int Psychogeriatr. 2000;12(3):389-401.
32. Blesa R. Galantamine: therapeutic effects beyond cognition. Dement Geriatr Cogn Disord. 2000;11(Suppl)1:28-34.
1. Irizarry M, Hyman B. Alzheimer’s disease. In: Principles of neuroepidemiology. Batchelor T, Cudkowicz M, eds. Boston: Butterworth-Heinemann, 2001:69-98.
2. Mesulam MM, Mufson EJ, Levey AI, Warner BH. Cholinergic innervation of cortex by the basal forebrain: Cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. J Comp Neurol. 1983a;214:170-197.
3. Drachman DA, Leavitt J. Human memory and the cholinergic system. A relationship to aging? Arch Neurol. 1974;30:113-121.
4. Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet. 1976;2:1403.-
5. Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR. Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol. 1981;10:122-126.
6. Higgins JPT, Flicker L. Lecithin and cognitive impairment. The Cochrane Database of Systematic Reviews. 2001.;
7. Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. The Tacrine Study Group. JAMA. 1994;271:985-991.
8. Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology. 2000;54:2262-2268.
9. Giacobini E. Cholinesterase inhibitors stabilize Alzheimer’s disease. Methods Find Exp Clin Pharmacol. 2000;22:609-613.
10. Irizarry MC, Hyman BT. Alzhemier Disease Therapeutics. J Neuropathology Exp Neurology. 2001;60:923-928.
11. Wilkinson DG. The pharmacology of donepezil: a new treatment of Alzheimer’s disease. Expert Opin Pharmacother. 1999;1:121-135.
12. Polinsky RJ. Clinical pharmacology of rivastigmine: a new-generation acetyl-cholinesterase inhibitor for the treatment of Alzheimer’s disease. Clin Ther. 1998;20:634-647.
13. Samochocki M, Zerlin M, Jostock R, et al. Galantamine is an allosterically potentiating ligand of the human alpha4/beta2 nAChR. Acta Neurol Scand. 2000(Suppl);;176:68-73.
14. Winblad B, Engedal K, Soininen H, Verhey F, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology. 2001;57:489-495.
15. Feldman H, Gauthier S, Hecker J, et al. Donepezil MSAD Study Investigators Group.A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology. 2001;57:613-620.
16. Farlow M, Anand R, Messina J, Jr, Hartman R, Veach J. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease. Eur Neurol. 2000;44:236-241.
17. Rogers S, Friedhoff L. Donepezil Study Group.The efficacy and safety of donepezil in patients with Alzhemier’s disease. Dementia. 1996;7:293-303.
18. Rogers S, Farlow M, Doody R, Morris R, Friedhoff L. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology. 1998;50:136-145.
19. Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, DalBianco P, Stahelin HB, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: International randomized controlled trial. BMJ. 1999;318:633-638.
20. Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology. 2000;54:2269-2276.
21. Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: Multicentre randomized controlled trial. Galantamine International - 1 Study Group. BMJ. 2000;321:1445-1449.
22. Knopman DS. Management of cognition and function: new results from the clinical trials programme of Aricept (R) (donepezil Hcl). Int J Neuropsychopharmacol. 2000;3:13-20.
23. Cummings JL, Donohue JA, Brooks RL. The relationship between donepezil and behavioral disturbances in patients with Alzheimer’s disease. Am J Geriatr Psychiatry. 2000;8:134-140.
24. Weiner MF, Martin-Cook K, Foster BM, Saine K, et al. Effects of donepezil on emotional/behavioral symptoms in Alzheimer’s disease patients. J Clin Psychiatry. 2000;487-492.
25. Rosler M, Retz W, Retz-Junginger P, Dennler HJ. Effects of two-year treatment with the cholinesterase inhibitor rivastigmine on behavioural symptoms in Alzheimer’s disease. Behav Neurol. 1998;11:211-216.
26. McKeith I, Del Ser T, Spano P, Emre M, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet. 2000;356(9247):2031-2036.
27. Fillit H, Gutterman EM, Lewis B. Donepezil use in managed Medicare: effect on health care costs and utilization. Clin Ther. 1999;21:2173-2185.
28. Neumann PJ, Hermann RC, Kuntz KM, Araki SS, Duff SB, Leon J, Berenbaum PA, et al. Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer’s disease. Neurology. 1999;52:1115-1116.
29. Hauber AB, Gnanasakthy A, Mauskopf JA. Savings in the cost of caring for patients with Alzheimer’s disease in Canada: an analysis of treatment with rivastigmine. Clin Ther. 2000;22:439-451.
30. Getsios D, Caro JJ, Caro G, Ishak K. The AHEAD Study Group. Assessment of health economics in Alzheimer’s disease (AHEAD): galantamine treatment in Canada. Neurology. 2001;57:972-978.
31. Fillit HM, Gutterman EM, Brooks RL. Impact of donepezil on caregiving burden for patients with Alzheimer’s disease. Int Psychogeriatr. 2000;12(3):389-401.
32. Blesa R. Galantamine: therapeutic effects beyond cognition. Dement Geriatr Cogn Disord. 2000;11(Suppl)1:28-34.