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Using antipsychotics in patients with dementia
Three keys can help you safely treat dementia’s difficult behavioral and psychological symptoms:
- Differentiate medical from psychiatric causes of patients’ distress.
- Use antipsychotics and other drugs as adjuncts to psychosocial treatments.
- Start low and go slow when titrating dosages.
Although no treatment reverses the pathophysiology of progressive neurodegenerative disorders, managing agitation and other behaviors can alleviate patient suffering and reduce caregiver stress. Based on the evidence and our experience, this article describes a practical approach, including a treatment algorithm and evidence of atypical antipsychotics’ efficacy and side effects in this patient population.
Algorithm Treating behavioral symptoms in patients with dementia
Dementia’s behavioral symptoms
An International Psychogeriatric Association consensus statement1 grouped dementia’s behavioral and psychological symptoms into two types:
- those usually assessed by interviewing patients and relatives—anxiety, depressed mood, hallucinations, and delusions
- those usually identified by observing patient behavior—aggression, screaming, restlessness, agitation, wandering, culturally inappropriate behaviors, sexual disinhibition, hoarding, cursing, and shadowing.
These behaviors in community-living patients are distressing to family members and increase the risk for caregiver burnout—the most common reason for placing older patients in long-term care. In the nursing home, dementia’s symptoms reduce patients’ quality of life; interfere with feeding, bathing, and dressing; and—when violent—may endanger staff and other patients.
Rule out a medical cause
Differential diagnosis. Behavioral symptoms in dementia tend to be unpredictable, which makes diagnosis and treatment challenging. The first step is to determine if a medical or psychiatric condition might account for the behavior. For instance:
- A patient with dementia may be agitated because of a distended bladder or arthritis but unable to communicate his or her pain in words.
- In mild dementia, a pre-existing psychiatric disorder such as schizophrenia might be causing a patient’s hallucinations or delusions.
- Pacing and restlessness may be drug side effects and might be controlled by reducing dosages or switching to less-activating agents.
Delirium is also a risk for older patients—especially those with degenerative neurologic disorders. Common triggers in older patients include acute illness such as a urinary tract infection or pneumonia, alcohol or benzodiazepine withdrawal, anticholinergic agents, medication changes, and dehydration.
Delirium is characterized by acute onset and fluctuating neuropsychiatric symptoms, including disturbed consciousness and changes in attention and cognition. Taking a careful history to learn the course of treatment and the patient’s baseline cognitive function can help you differentiate dementia from delirium. Family members, physicians, and nursing staff are valuable sources of this information.
Use antipsychotics as adjuncts
Psychosocial interventions. After medical causes have been ruled out, consensus guidelines2 recommend psychosocial interventions as first-line treatment of dementia’s behavioral symptoms (Algorithm). Suggested interventions for patients and caregivers are listed in Table 1.3
Antipsychotics. For patients who respond inadequately to psychosocial measures, the next step is to add an atypical antipsychotic. Because of side effects, conventional antipsychotics are not recommended for patients with dementia.
When prescribing atypicals, remember that older adults:
- are more sensitive to side effects than younger adults
- require lower starting and target dosages
- exhibit heterogeneity of response.
Older patients’ medical status can range from “fit” to “frail,” which influences individual response to medications. Generally, age-related changes in the way their bodies metabolize drugs account for older patients’ increased sensitivity to drug side effects (Box).4-11
Atypical antipsychotics and dosages that have been shown benefit for managing behavioral symptoms in older patients with dementia include:
- risperidone, 0.5 to 1.5 mg/d12
- olanzapine, 5 to 10 mg/d13
- quetiapine, 25 to 350 mg/d14 (Table 2).15,16
Start with low dosages, and titrate slowly. Increase once or twice a week until the lowest effective dosage is reached.
Augmenting agents. If antipsychotic monotherapy fails to achieve an adequate response or if side effects limit dosing, adjunctive agents may be added with caution. Augmenting agents that have shown benefit in some patients with dementia include:
- mood stabilizers such as divalproex17 or carbamazepine18
- cholinesterase inhibitors, such as donepezil, rivastigmine, or galantamine.19
Start divalproex at 125 mg bid or carbamazepine at 100 mg bid and titrate to effect. Concomitant carbamazepine will decrease blood levels of risperidone, olanzapine, and quetiapine because of hepatic enzyme induction.20
Start donepezil at 5 mg once daily and increase after 4 to 6 weeks to 10 mg qd. When using rivastigmine, start with 1.5 mg bid and titrate to 9 to 12 mg/d in divided doses. Start galantamine at 4 mg bid and increase after 1 month to 8 mg bid.
Table 1
Suggested psychosocial interventions for older patients with dementia
Communicate clearly
|
Minimize the impact of sensory deficits
|
Modify environment when necessary
|
Encourage consistent daily routines
|
Optimize social/physical stimulation
|
Encourage caregiver to:
|
Antipsychotic side effects
Atypical antipsychotics are more effective than conventional agents in treating negative symptoms and are associated with lower rates of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD).21
Tardive dyskinesia. All antipsychotics can cause TD, although the risk is about 10 times greater with conventionals than atypicals. With conventionals, the annual cumulative TD incidence for young adults is 4 to 5%,22 and rates are much higher for middle-aged and older adults receiving chronic therapy:
- 29% after 1 year
- 50% after 2 years
- 63% after 3 years.23
In older patients, use atypical rather than conventional antipsychotics to minimize TD risk. Observe carefully; if TD symptoms occur, cautiously withdraw the antipsychotic and consider trying another agent.
Other risks. Atypical antipsychotics may cause sedation, orthostatic hypotension (with an increased risk for falls), increased serum prolactin, and weight gain (Table 2).
Weight gain from atypical antipsychotics has been associated with adverse effects on glucose metabolism and increased risk for type 2 diabetes.24 Some might argue that weight gain associated with olanzapine and other atypicals might benefit low-weight older patients. The frail elderly need to increase muscle mass, however, and the atypicals are associated with increases in fat mass.
Increased serum prolactin with risperidone theoretically could lead to loss of bone density, but evidence of this effect in older patients does not exist.
Start low, go slow
Clozapine may help control treatment-resistant psychosis in patients with schizophrenia and manage patients with severe TD.25 However, clozapine’s increased risk of agranulocytosis, neurologic side effects (seizures, sedation, confusion), and anticholinergic effects limit its use in older patients, particularly those with neurodegenerative disorders (Table 2).
Dosing. In rare cases when using clozapine in older patients, start with 6.25 to 12.5 mg/d. Increase by 6.25 to 12.5 mg once or twice a week to 50 to 100 mg/d.
Risperidone has been used to treat agitation in older patients with dementia in two small studies:
In a 9-week, open-label trial, 15 patients (mean age 78) with dementia were given risperidone, 0.5 to 3 mg/d. Agitation improved significantly, as measured by the Cohen-Mansfield Agitation Inventory (CMAI)—a 29-item questionnaire completed by caregivers.26 CMAI scores at study’s end averaged 49.5, compared with 70.5 at baseline.27
A 12-week, placebo-controlled, doubleblind study examined risperidone—0.5, 1, or 2 mg/d—in 625 institutionalized patients (mean age 83) with dementia and agitation. Ninety-six patients had Functional Assessment Staging Rating Scale scores of 6A, indicating moderate to severe dementia. In patients receiving risperidone, these behavioral measures were significantly reduced:
- Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) total scores, which measure behavior severity
- BEHAVE-AD psychosis subscale scores
- BEHAVE-AD aggressiveness scores
- CMAI verbal and aggression scores.
Adverse effects were reported at 82% for all three risperidone dosages and 85% for placebo. Side effects including somnolence, EPS, and peripheral edema were dose-related.12
Another trial compared risperidone or haloperidol, 0.5 to 4 mg/d, with placebo in treating 344 patients with behavioral symptoms of dementia. After 12 weeks of risperidone, mean dosage 1.1 mg/d:
- mean total BEHAVE-AD score decreased by 53%, compared with 37% in the placebo group
- CMAI score decreased by 32%, compared with 18% in the placebo group.
EPS were more severe with haloperidol than with risperidone or placebo.28
Risk of stroke. A small but significantly increased incidence of stroke and stroke-like events was recently reported in older patients with dementia when treated with risperidone. These events occurred in double-blind, placebocontrolled trials in patients (mean age 82) with Alzheimer’s, vascular, and mixed dementias.
Pharmacokinetic changes can influence concentrations of drugs in tissue compartments over time. Drug absorption declines with normal aging, but a clinically significant decrease in total absorption of psychotropics appears not to occur.13
In the liver, lipid-soluble psychotropics are metabolized into pharmacologically active or inactive metabolites. Some metabolic pathways, such as demethylation, may be influenced by age, leading to increased plasma concentrations of drugs and their metabolites.14,15 However, hydroxylation tends not to be affected by age.16
The ratio of body fat to water increases with aging,13 increasing the volume of distribution for lipid-soluble psychotropics. An age-related decrease in glomerular filtration accounts in part for increased accumulation of hydrophilic metabolites in some older patients.17,18
Pharmacodynamic changes with aging occur in neurotransmitter systems within cellular processing, such as at receptor or reuptake levels.19 These changes may exaggerate drug-drug interactions or affect complex neurotransmitter interactions.
The number of neurons in nigrostriatal pathways declines with age. Decreases are also seen in tyrosine hydroxylase activity, presynaptic dopamine D2 receptors, and dopamine levels—which may be particularly relevant to a discussion of antipsychotic medications.20
The net effect of these changes is the need to prescribe lower-than-usual starting and target dosages of many medications, including antipsychotics.
Most patients who experienced cerebrovascular events had one or more stroke risk factors, including diabetes, hypertension, atrial fibrillation, heart arrhythmia, atherosclerosis, or heart failure. They did not show a pattern of reduced blood pressure or orthostatic changes.12,29
Table 2
Antipsychotic side effects and dosages in older patients with dementia*
| Side effect | Clozapine (6.25 to 100 mg/d) | Risperidone (0.5 to 1.5 mg/d) | Olanzapine (5 to 10 mg/d) | Quetiapine (25 to 350 mg/d) |
|---|---|---|---|---|
| Orthostasis | ++++ | ++++ | +++ | ++ |
| Sedation | +++++ | ++ | +++ | ++ |
| Prolactin increase | 0 | +++ | + | 0 |
| Weight gain | ++++ | + | +++ | + |
| EPS | 0/+ | ++ | + | 0/+ |
| Tardive dyskinesia | 0 | + | + | ? |
| Anticholinergic effects | ++++ | + | + | 0 |
| Seizure risk | +++ | + | + | + |
| Hematologic effects | +++ | + | + | + |
| Source: Adapted from references 15 and 16. | ||||
| * Side-effect profiles and recommended dosages of ziprasidone and aripiprazole in older patients are not yet established. | ||||
| EPS: Extrapyramidal symptoms | ||||
| Key: | ||||
| 0 = none | ||||
| + = slight | ||||
| +++ = mild | ||||
| +++++ = marked | ||||
| 0/+ = none to slight | ||||
| ++ = very mild | ||||
| ++++ = moderate | ||||
Dosing. For older patients with dementia and psychosis, start risperidone at 0.25 to 0.5 mg/d and increase by no more than 0.25 to 0.5 mg once or twice per week. Do not exceed 3 mg/d. For agitation, a 1998 Expert Consensus Guideline Series panel2 recommended starting risperidone at 0.25 to 0.5 mg/d and increasing to an average of 0.5 to 1.5 mg/d.
Olanzapine. Two double-blind, placebo-controlled studies have examined olanzapine in treating agitation associated with dementia.
Saterlee et al30 compared olanzapine, mean 2.4 mg/d, with placebo in outpatients (mean age 79) with Alzheimer’s disease and psychosis. No significant differences were noted in hepatic transaminase levels, leukopenia, EPS, or orthostatic changes.
In a later study,13 nursing home patients (mean age 83) with Alzheimer’s disease, psychosis, and agitation were randomly assigned to receive olanzapine—5, 10, or 15 mg/d—or placebo. After 6 weeks, patients receiving olanzapine, 5 or 10 mg/d, showed significant improvement in Neuropsychiatric Inventory (NPI) total core scores. Olanzapine, 15 mg/d, was not significantly more effective than placebo.
Adverse events such as somnolence and abnormal gait occurred more often with olanzapine than placebo. The somnolence rate with olanzapine was 14% for 5 mg/d and 13% for 10 mg/d, compared with 3% for placebo. For abnormal gait, the rate with olanzapine was 11% for 5 mg/d and 7% for 10 mg/d, compared with 1% for placebo.
Dosing. Start olanzapine at 2.5 mg/d, and increase after 1 to 3 days to 5 mg/d. If symptoms are not adequately controlled, titrate by 2.5-mg increments to 10 mg/d.
Quetiapine. One open-label study14 examined using quetiapine in older patients with psychotic disorders. The study enrolled 184 patients (mean age 76) with Alzheimer’s disease, Parkinson’s disease, schizophrenia, vascular dementia, schizoaffective disorder, bipolar disorder, or major depression. Before the trial, patients were taking various conventional and atypical antipsychotics.
Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions (CGI) scores improved significantly after 52 weeks of quetiapine, median 137.5 mg/d. BPRS scores improved 20% in 49% of patients who completed the study.
Less than one-half (48%) of enrolled patients completed the study. Reasons for withdrawal included lack of efficacy (19%), adverse events or illness (15%; adverse events alone, 11%), lost to follow-up (13%), protocol noncompliance (3%), or diminished need for treatment (2%).
EPS occurred in 13% of patients. Mean total scores on the Simpson-Angus Rating Scale for Extrapyramidal Side Effects decreased 1.8 points, indicating reduced parkinsonian symptoms.
Dosing. Start quetiapine at 25 mg once at bedtime or bid; increase in 25-mg increments until the lowest effective dosage is achieved.
Ziprasidone. Little data exist on using ziprasidone in long-term care. In one recent study,31 ziprasidone (mean 100 mg/d) was given to 62 patients ages 64 to 92 with medical illnesses plus major depression, bipolar disorder, schizoaffective disorder, Alzheimer’s disease, or multi-infarct dementia. A retrospective chart review of 10 patients showed decreased agitation, as mean NPI scores declined from 76 to 33.
Sedation was the most common side effect. QTc findings, postural hypotension, and syncope rates did not change. Despite its limitations, this study suggests that ziprasidone is safe and effective in treating psychosis associated with dementia or other disorders.
Aripiprazole. As with ziprasidone, little data exist to guide the use of aripiprazole in older patients. In a randomized preliminary trial,32 192 noninstitutionalized patients with Alzheimer’s disease and psychosis were treated for 10 weeks with aripiprazole, mean 10 mg/d, or placebo.
At 8 and 10 weeks, BPRS psychosis subscale scores improved significantly in patients taking aripiprazole, compared with placebo. EPS and akathisia improved, and somnolence was the most common side effect. Although this study enrolled noninstitutionalized patients with dementia, the results suggest that aripiprazole may help treat long-term care residents with neurodegenerative disorders and behavioral disturbances.
Related resources
- Zaraa AS. Dementia update: Pharmacologic management of agitation and psychosis in older demented patients. Geriatrics 2003;58(10):48-53.
- Mills EJ, Chow TW. Randomized controlled trials in long-term care of residents with dementia: a systematic review. J Am Med Dir Assoc 2003;4(6):302-7.
- Alzheimer’s Association. Treating agitation. www.alz.org/PhysCare/Treating/agitation.htm
Drug brand names
- Aripiprazole • Abilify
- Carbamazepine • Tegretol
- Clozapine • Clozaril
- Donepezil • Aricept
- Galantamine • Reminyl
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Rivastigmine • Exelon
- Valproate • Depakote
- Ziprasidone • Geodon
Disclosure
Dr. Kasckow receives research support from, is a consultant to, or is a speaker for Eli Lilly & Co., Forest Laboratories, Solvay Pharmaceuticals, AstraZeneca Pharmaceuticals, Organon, Janssen Pharmaceutica, and Pfizer Inc.
Dr. Mulchahey reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Mohamed receives research support form Forest Laboratories and is a speaker for Eli Lilly & Co.
1. Finkel S, Costa e Silva J, Cohen G, et al. Behavioral and psychological symptoms of dementia: a consensus statement on current knowledge and implications for research and treatment. Am J Geriatr Psychiatry 1998;6:97-100.
2. The Expert Consensus Panel for Agitation in Dementia. Treatment of agitation in older persons with dementia. Postgrad Med 1998;4(suppl):1-88.
3. Cohen-Mansfield J. Nonpharmacologic interventions for inappropriate behaviors in dementia: a review, summary, and critique. Am J Geriatr Psychiatry 2001;9(4):361-81.
4. Davidson J. Pharmacologic treatment. In: Busse E, Blazer D (eds). Textbook of geriatric psychiatry (2nd ed). Washington DC: American Psychiatric Publishing, 1996:359-79.
5. Nies A, Robinson DS, Friedman MJ, et al. Relationship between age and tricyclic antidepressant plasma levels. Am J Psychiatry 1977;134(7):790-3.
6. Greenblatt DJ, Shader RJ. Benzodiazepine kinetics in the elderly. In: Usdin E (ed). Clinical pharmacology in psychiatry. New York: Elsevier, 1981;174-81.
7. Pollock BG, Perel JM, Altieri LP, et al. Debrisoquine hydroxylation phenotyping in geriatric psychopharmacology. Psychopharmacol Bull. 1992;28(2):163-8.
8. Nelson JC, Atillasoy E, Mazure C, Jatlow PI. Hydroxydesipramine in the elderly. J Clin Psychopharmacol 1988;8(6):428-33.
9. Young RC, Alexopoulos GS, Shamoian CA, et al. Plasma 10-hydroxynortriptyline in elderly depressed patients. Clin Pharmacol Ther 1984;35(4):540-4.
10. Cantillon M, Molchan SE, Little J. Pharmacological and neuroendocrine probes in neuropsychiatric illness. In: Coffey CE, Cummings JL (eds). Textbook of geriatric neuropsychiatry. Washington, DC: American Psychiatric Publishing, 1994.
11. Young RC, Meyers BS. Psychopharmacology. In: Sadovoy J, Lazarus LW, Jarvik LF, Grossberg GT (eds). Comprehensive review of geriatric psychiatry. Washington DC: American Psychiatric Publishing, 1996;755-817.
12. Katz IR, Jeste DV, Mintzer JE, et al. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. J Clin Psychiatry 1999;60(2):107-15.
13. Street JS, Clark WS, Gannon KS, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group. Arch Gen Psychiatry 2000;57(10):968-76.
14. Tariot PN, Salzman C, Yeung PP, et al. Long-term use of quetiapine in elderly patients with psychotic disorders. Clin Ther 2000;22(9):1068-84.
15. Casey DE. The relationship of pharmacology to side effects. J Clin Psychiatry 1997;58(suppl):55-62.
16. Pickar D. Prospects for pharmacotherapy of schizophrenia. Lancet 1995;345:557-62.
17. Kasckow JW, McElroy SL, Cameron RL, et al. A pilot study on the use of divalproex sodium in the treatment of behavioral agitation in elderly patients with dementia: assessment with the BEHAVE-AD and CGI rating scales. Curr Ther Res 1997;58(12):981-9.
18. Tariot PN, Erb R, Podgorski CA, et al. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry 1998;155(1):54-61.
19. Kasckow JW. Cognitive enhancers for dementia: do they work? Current Psychiatry 2002;1(3):22-8.
20. Lacy C, Armstrong L, Goldman M, Lance L. (eds) Lexicomp drug information handbook. Hudson, OH: Lexicomp, 2003-2004:1225-27, 1189-90, 1026-27.
21. Jeste DV, Lacro JP, Bailey A, et al. Lower incidence of tardive dyskinesia with risperidone compared with haloperidol in older patients. J Am Geriatr Soc 1999;47(6):716-19.
22. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45(9):789-96.
23. Jeste DV, Caligiuri MP, Paulsen JS, et al. Risk of tardive dyskinesia in older patients. A prospective longitudinal study of 266 outpatients. Arch Gen Psychiatry 1995;52(9):756-65.
24. Sernyak MJ, Leslie DL, Alarcon RD, et al. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002;159:561-6.
25. Chengappa KN, Baker RW, Kreinbrook SB, Adair D. Clozapine use in female geriatric patients with psychoses. JGeriatr Psychiatry Neurol 1995;8(1):12-15.
26. Cohen-Mansfield J, Marx MS, Rosenthal AS. A description of agitation in the nursing home. J Gerontol 1989;44(3):M77-84.
27. Lavretsky H, Sultzer D. A structured trial of risperidone for the treatment of agitation in dementia. Am J Geriatr Psychiatry 1998;6(2):127-35.
28. De Deyn PP, Rabheru K, Rasmussen A, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999;53(5):946-55.
29. Brodaty H, Ames D, Snowdon J, et al. A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia. J Clin Psychiatry 2003;64(2):134-43.
30. Satterlee W, Reams SG, Burns PR, et al. A clinical update on olanzapine treatment in schizophrenia and in elderly Alzheimer’s disease patients (abstract). Psychopharmacol Bull 1995;31:534.-
31. Berkowitz A. Ziprasidone for elderly dementia: a case series (abstract). San Francisco, CA: American Psychiatric Association annual meeting, 2003.
32. De Deyn PP, Jeste D, Auby P, Carson W. Aripiprazole in dementia of the Alzheimer’s type (abstract). Honolulu, HI: American Association for Geriatric Psychiatry annual meeting, 2003.
Three keys can help you safely treat dementia’s difficult behavioral and psychological symptoms:
- Differentiate medical from psychiatric causes of patients’ distress.
- Use antipsychotics and other drugs as adjuncts to psychosocial treatments.
- Start low and go slow when titrating dosages.
Although no treatment reverses the pathophysiology of progressive neurodegenerative disorders, managing agitation and other behaviors can alleviate patient suffering and reduce caregiver stress. Based on the evidence and our experience, this article describes a practical approach, including a treatment algorithm and evidence of atypical antipsychotics’ efficacy and side effects in this patient population.
Algorithm Treating behavioral symptoms in patients with dementia
Dementia’s behavioral symptoms
An International Psychogeriatric Association consensus statement1 grouped dementia’s behavioral and psychological symptoms into two types:
- those usually assessed by interviewing patients and relatives—anxiety, depressed mood, hallucinations, and delusions
- those usually identified by observing patient behavior—aggression, screaming, restlessness, agitation, wandering, culturally inappropriate behaviors, sexual disinhibition, hoarding, cursing, and shadowing.
These behaviors in community-living patients are distressing to family members and increase the risk for caregiver burnout—the most common reason for placing older patients in long-term care. In the nursing home, dementia’s symptoms reduce patients’ quality of life; interfere with feeding, bathing, and dressing; and—when violent—may endanger staff and other patients.
Rule out a medical cause
Differential diagnosis. Behavioral symptoms in dementia tend to be unpredictable, which makes diagnosis and treatment challenging. The first step is to determine if a medical or psychiatric condition might account for the behavior. For instance:
- A patient with dementia may be agitated because of a distended bladder or arthritis but unable to communicate his or her pain in words.
- In mild dementia, a pre-existing psychiatric disorder such as schizophrenia might be causing a patient’s hallucinations or delusions.
- Pacing and restlessness may be drug side effects and might be controlled by reducing dosages or switching to less-activating agents.
Delirium is also a risk for older patients—especially those with degenerative neurologic disorders. Common triggers in older patients include acute illness such as a urinary tract infection or pneumonia, alcohol or benzodiazepine withdrawal, anticholinergic agents, medication changes, and dehydration.
Delirium is characterized by acute onset and fluctuating neuropsychiatric symptoms, including disturbed consciousness and changes in attention and cognition. Taking a careful history to learn the course of treatment and the patient’s baseline cognitive function can help you differentiate dementia from delirium. Family members, physicians, and nursing staff are valuable sources of this information.
Use antipsychotics as adjuncts
Psychosocial interventions. After medical causes have been ruled out, consensus guidelines2 recommend psychosocial interventions as first-line treatment of dementia’s behavioral symptoms (Algorithm). Suggested interventions for patients and caregivers are listed in Table 1.3
Antipsychotics. For patients who respond inadequately to psychosocial measures, the next step is to add an atypical antipsychotic. Because of side effects, conventional antipsychotics are not recommended for patients with dementia.
When prescribing atypicals, remember that older adults:
- are more sensitive to side effects than younger adults
- require lower starting and target dosages
- exhibit heterogeneity of response.
Older patients’ medical status can range from “fit” to “frail,” which influences individual response to medications. Generally, age-related changes in the way their bodies metabolize drugs account for older patients’ increased sensitivity to drug side effects (Box).4-11
Atypical antipsychotics and dosages that have been shown benefit for managing behavioral symptoms in older patients with dementia include:
- risperidone, 0.5 to 1.5 mg/d12
- olanzapine, 5 to 10 mg/d13
- quetiapine, 25 to 350 mg/d14 (Table 2).15,16
Start with low dosages, and titrate slowly. Increase once or twice a week until the lowest effective dosage is reached.
Augmenting agents. If antipsychotic monotherapy fails to achieve an adequate response or if side effects limit dosing, adjunctive agents may be added with caution. Augmenting agents that have shown benefit in some patients with dementia include:
- mood stabilizers such as divalproex17 or carbamazepine18
- cholinesterase inhibitors, such as donepezil, rivastigmine, or galantamine.19
Start divalproex at 125 mg bid or carbamazepine at 100 mg bid and titrate to effect. Concomitant carbamazepine will decrease blood levels of risperidone, olanzapine, and quetiapine because of hepatic enzyme induction.20
Start donepezil at 5 mg once daily and increase after 4 to 6 weeks to 10 mg qd. When using rivastigmine, start with 1.5 mg bid and titrate to 9 to 12 mg/d in divided doses. Start galantamine at 4 mg bid and increase after 1 month to 8 mg bid.
Table 1
Suggested psychosocial interventions for older patients with dementia
Communicate clearly
|
Minimize the impact of sensory deficits
|
Modify environment when necessary
|
Encourage consistent daily routines
|
Optimize social/physical stimulation
|
Encourage caregiver to:
|
Antipsychotic side effects
Atypical antipsychotics are more effective than conventional agents in treating negative symptoms and are associated with lower rates of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD).21
Tardive dyskinesia. All antipsychotics can cause TD, although the risk is about 10 times greater with conventionals than atypicals. With conventionals, the annual cumulative TD incidence for young adults is 4 to 5%,22 and rates are much higher for middle-aged and older adults receiving chronic therapy:
- 29% after 1 year
- 50% after 2 years
- 63% after 3 years.23
In older patients, use atypical rather than conventional antipsychotics to minimize TD risk. Observe carefully; if TD symptoms occur, cautiously withdraw the antipsychotic and consider trying another agent.
Other risks. Atypical antipsychotics may cause sedation, orthostatic hypotension (with an increased risk for falls), increased serum prolactin, and weight gain (Table 2).
Weight gain from atypical antipsychotics has been associated with adverse effects on glucose metabolism and increased risk for type 2 diabetes.24 Some might argue that weight gain associated with olanzapine and other atypicals might benefit low-weight older patients. The frail elderly need to increase muscle mass, however, and the atypicals are associated with increases in fat mass.
Increased serum prolactin with risperidone theoretically could lead to loss of bone density, but evidence of this effect in older patients does not exist.
Start low, go slow
Clozapine may help control treatment-resistant psychosis in patients with schizophrenia and manage patients with severe TD.25 However, clozapine’s increased risk of agranulocytosis, neurologic side effects (seizures, sedation, confusion), and anticholinergic effects limit its use in older patients, particularly those with neurodegenerative disorders (Table 2).
Dosing. In rare cases when using clozapine in older patients, start with 6.25 to 12.5 mg/d. Increase by 6.25 to 12.5 mg once or twice a week to 50 to 100 mg/d.
Risperidone has been used to treat agitation in older patients with dementia in two small studies:
In a 9-week, open-label trial, 15 patients (mean age 78) with dementia were given risperidone, 0.5 to 3 mg/d. Agitation improved significantly, as measured by the Cohen-Mansfield Agitation Inventory (CMAI)—a 29-item questionnaire completed by caregivers.26 CMAI scores at study’s end averaged 49.5, compared with 70.5 at baseline.27
A 12-week, placebo-controlled, doubleblind study examined risperidone—0.5, 1, or 2 mg/d—in 625 institutionalized patients (mean age 83) with dementia and agitation. Ninety-six patients had Functional Assessment Staging Rating Scale scores of 6A, indicating moderate to severe dementia. In patients receiving risperidone, these behavioral measures were significantly reduced:
- Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) total scores, which measure behavior severity
- BEHAVE-AD psychosis subscale scores
- BEHAVE-AD aggressiveness scores
- CMAI verbal and aggression scores.
Adverse effects were reported at 82% for all three risperidone dosages and 85% for placebo. Side effects including somnolence, EPS, and peripheral edema were dose-related.12
Another trial compared risperidone or haloperidol, 0.5 to 4 mg/d, with placebo in treating 344 patients with behavioral symptoms of dementia. After 12 weeks of risperidone, mean dosage 1.1 mg/d:
- mean total BEHAVE-AD score decreased by 53%, compared with 37% in the placebo group
- CMAI score decreased by 32%, compared with 18% in the placebo group.
EPS were more severe with haloperidol than with risperidone or placebo.28
Risk of stroke. A small but significantly increased incidence of stroke and stroke-like events was recently reported in older patients with dementia when treated with risperidone. These events occurred in double-blind, placebocontrolled trials in patients (mean age 82) with Alzheimer’s, vascular, and mixed dementias.
Pharmacokinetic changes can influence concentrations of drugs in tissue compartments over time. Drug absorption declines with normal aging, but a clinically significant decrease in total absorption of psychotropics appears not to occur.13
In the liver, lipid-soluble psychotropics are metabolized into pharmacologically active or inactive metabolites. Some metabolic pathways, such as demethylation, may be influenced by age, leading to increased plasma concentrations of drugs and their metabolites.14,15 However, hydroxylation tends not to be affected by age.16
The ratio of body fat to water increases with aging,13 increasing the volume of distribution for lipid-soluble psychotropics. An age-related decrease in glomerular filtration accounts in part for increased accumulation of hydrophilic metabolites in some older patients.17,18
Pharmacodynamic changes with aging occur in neurotransmitter systems within cellular processing, such as at receptor or reuptake levels.19 These changes may exaggerate drug-drug interactions or affect complex neurotransmitter interactions.
The number of neurons in nigrostriatal pathways declines with age. Decreases are also seen in tyrosine hydroxylase activity, presynaptic dopamine D2 receptors, and dopamine levels—which may be particularly relevant to a discussion of antipsychotic medications.20
The net effect of these changes is the need to prescribe lower-than-usual starting and target dosages of many medications, including antipsychotics.
Most patients who experienced cerebrovascular events had one or more stroke risk factors, including diabetes, hypertension, atrial fibrillation, heart arrhythmia, atherosclerosis, or heart failure. They did not show a pattern of reduced blood pressure or orthostatic changes.12,29
Table 2
Antipsychotic side effects and dosages in older patients with dementia*
| Side effect | Clozapine (6.25 to 100 mg/d) | Risperidone (0.5 to 1.5 mg/d) | Olanzapine (5 to 10 mg/d) | Quetiapine (25 to 350 mg/d) |
|---|---|---|---|---|
| Orthostasis | ++++ | ++++ | +++ | ++ |
| Sedation | +++++ | ++ | +++ | ++ |
| Prolactin increase | 0 | +++ | + | 0 |
| Weight gain | ++++ | + | +++ | + |
| EPS | 0/+ | ++ | + | 0/+ |
| Tardive dyskinesia | 0 | + | + | ? |
| Anticholinergic effects | ++++ | + | + | 0 |
| Seizure risk | +++ | + | + | + |
| Hematologic effects | +++ | + | + | + |
| Source: Adapted from references 15 and 16. | ||||
| * Side-effect profiles and recommended dosages of ziprasidone and aripiprazole in older patients are not yet established. | ||||
| EPS: Extrapyramidal symptoms | ||||
| Key: | ||||
| 0 = none | ||||
| + = slight | ||||
| +++ = mild | ||||
| +++++ = marked | ||||
| 0/+ = none to slight | ||||
| ++ = very mild | ||||
| ++++ = moderate | ||||
Dosing. For older patients with dementia and psychosis, start risperidone at 0.25 to 0.5 mg/d and increase by no more than 0.25 to 0.5 mg once or twice per week. Do not exceed 3 mg/d. For agitation, a 1998 Expert Consensus Guideline Series panel2 recommended starting risperidone at 0.25 to 0.5 mg/d and increasing to an average of 0.5 to 1.5 mg/d.
Olanzapine. Two double-blind, placebo-controlled studies have examined olanzapine in treating agitation associated with dementia.
Saterlee et al30 compared olanzapine, mean 2.4 mg/d, with placebo in outpatients (mean age 79) with Alzheimer’s disease and psychosis. No significant differences were noted in hepatic transaminase levels, leukopenia, EPS, or orthostatic changes.
In a later study,13 nursing home patients (mean age 83) with Alzheimer’s disease, psychosis, and agitation were randomly assigned to receive olanzapine—5, 10, or 15 mg/d—or placebo. After 6 weeks, patients receiving olanzapine, 5 or 10 mg/d, showed significant improvement in Neuropsychiatric Inventory (NPI) total core scores. Olanzapine, 15 mg/d, was not significantly more effective than placebo.
Adverse events such as somnolence and abnormal gait occurred more often with olanzapine than placebo. The somnolence rate with olanzapine was 14% for 5 mg/d and 13% for 10 mg/d, compared with 3% for placebo. For abnormal gait, the rate with olanzapine was 11% for 5 mg/d and 7% for 10 mg/d, compared with 1% for placebo.
Dosing. Start olanzapine at 2.5 mg/d, and increase after 1 to 3 days to 5 mg/d. If symptoms are not adequately controlled, titrate by 2.5-mg increments to 10 mg/d.
Quetiapine. One open-label study14 examined using quetiapine in older patients with psychotic disorders. The study enrolled 184 patients (mean age 76) with Alzheimer’s disease, Parkinson’s disease, schizophrenia, vascular dementia, schizoaffective disorder, bipolar disorder, or major depression. Before the trial, patients were taking various conventional and atypical antipsychotics.
Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions (CGI) scores improved significantly after 52 weeks of quetiapine, median 137.5 mg/d. BPRS scores improved 20% in 49% of patients who completed the study.
Less than one-half (48%) of enrolled patients completed the study. Reasons for withdrawal included lack of efficacy (19%), adverse events or illness (15%; adverse events alone, 11%), lost to follow-up (13%), protocol noncompliance (3%), or diminished need for treatment (2%).
EPS occurred in 13% of patients. Mean total scores on the Simpson-Angus Rating Scale for Extrapyramidal Side Effects decreased 1.8 points, indicating reduced parkinsonian symptoms.
Dosing. Start quetiapine at 25 mg once at bedtime or bid; increase in 25-mg increments until the lowest effective dosage is achieved.
Ziprasidone. Little data exist on using ziprasidone in long-term care. In one recent study,31 ziprasidone (mean 100 mg/d) was given to 62 patients ages 64 to 92 with medical illnesses plus major depression, bipolar disorder, schizoaffective disorder, Alzheimer’s disease, or multi-infarct dementia. A retrospective chart review of 10 patients showed decreased agitation, as mean NPI scores declined from 76 to 33.
Sedation was the most common side effect. QTc findings, postural hypotension, and syncope rates did not change. Despite its limitations, this study suggests that ziprasidone is safe and effective in treating psychosis associated with dementia or other disorders.
Aripiprazole. As with ziprasidone, little data exist to guide the use of aripiprazole in older patients. In a randomized preliminary trial,32 192 noninstitutionalized patients with Alzheimer’s disease and psychosis were treated for 10 weeks with aripiprazole, mean 10 mg/d, or placebo.
At 8 and 10 weeks, BPRS psychosis subscale scores improved significantly in patients taking aripiprazole, compared with placebo. EPS and akathisia improved, and somnolence was the most common side effect. Although this study enrolled noninstitutionalized patients with dementia, the results suggest that aripiprazole may help treat long-term care residents with neurodegenerative disorders and behavioral disturbances.
Related resources
- Zaraa AS. Dementia update: Pharmacologic management of agitation and psychosis in older demented patients. Geriatrics 2003;58(10):48-53.
- Mills EJ, Chow TW. Randomized controlled trials in long-term care of residents with dementia: a systematic review. J Am Med Dir Assoc 2003;4(6):302-7.
- Alzheimer’s Association. Treating agitation. www.alz.org/PhysCare/Treating/agitation.htm
Drug brand names
- Aripiprazole • Abilify
- Carbamazepine • Tegretol
- Clozapine • Clozaril
- Donepezil • Aricept
- Galantamine • Reminyl
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Rivastigmine • Exelon
- Valproate • Depakote
- Ziprasidone • Geodon
Disclosure
Dr. Kasckow receives research support from, is a consultant to, or is a speaker for Eli Lilly & Co., Forest Laboratories, Solvay Pharmaceuticals, AstraZeneca Pharmaceuticals, Organon, Janssen Pharmaceutica, and Pfizer Inc.
Dr. Mulchahey reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Mohamed receives research support form Forest Laboratories and is a speaker for Eli Lilly & Co.
Three keys can help you safely treat dementia’s difficult behavioral and psychological symptoms:
- Differentiate medical from psychiatric causes of patients’ distress.
- Use antipsychotics and other drugs as adjuncts to psychosocial treatments.
- Start low and go slow when titrating dosages.
Although no treatment reverses the pathophysiology of progressive neurodegenerative disorders, managing agitation and other behaviors can alleviate patient suffering and reduce caregiver stress. Based on the evidence and our experience, this article describes a practical approach, including a treatment algorithm and evidence of atypical antipsychotics’ efficacy and side effects in this patient population.
Algorithm Treating behavioral symptoms in patients with dementia
Dementia’s behavioral symptoms
An International Psychogeriatric Association consensus statement1 grouped dementia’s behavioral and psychological symptoms into two types:
- those usually assessed by interviewing patients and relatives—anxiety, depressed mood, hallucinations, and delusions
- those usually identified by observing patient behavior—aggression, screaming, restlessness, agitation, wandering, culturally inappropriate behaviors, sexual disinhibition, hoarding, cursing, and shadowing.
These behaviors in community-living patients are distressing to family members and increase the risk for caregiver burnout—the most common reason for placing older patients in long-term care. In the nursing home, dementia’s symptoms reduce patients’ quality of life; interfere with feeding, bathing, and dressing; and—when violent—may endanger staff and other patients.
Rule out a medical cause
Differential diagnosis. Behavioral symptoms in dementia tend to be unpredictable, which makes diagnosis and treatment challenging. The first step is to determine if a medical or psychiatric condition might account for the behavior. For instance:
- A patient with dementia may be agitated because of a distended bladder or arthritis but unable to communicate his or her pain in words.
- In mild dementia, a pre-existing psychiatric disorder such as schizophrenia might be causing a patient’s hallucinations or delusions.
- Pacing and restlessness may be drug side effects and might be controlled by reducing dosages or switching to less-activating agents.
Delirium is also a risk for older patients—especially those with degenerative neurologic disorders. Common triggers in older patients include acute illness such as a urinary tract infection or pneumonia, alcohol or benzodiazepine withdrawal, anticholinergic agents, medication changes, and dehydration.
Delirium is characterized by acute onset and fluctuating neuropsychiatric symptoms, including disturbed consciousness and changes in attention and cognition. Taking a careful history to learn the course of treatment and the patient’s baseline cognitive function can help you differentiate dementia from delirium. Family members, physicians, and nursing staff are valuable sources of this information.
Use antipsychotics as adjuncts
Psychosocial interventions. After medical causes have been ruled out, consensus guidelines2 recommend psychosocial interventions as first-line treatment of dementia’s behavioral symptoms (Algorithm). Suggested interventions for patients and caregivers are listed in Table 1.3
Antipsychotics. For patients who respond inadequately to psychosocial measures, the next step is to add an atypical antipsychotic. Because of side effects, conventional antipsychotics are not recommended for patients with dementia.
When prescribing atypicals, remember that older adults:
- are more sensitive to side effects than younger adults
- require lower starting and target dosages
- exhibit heterogeneity of response.
Older patients’ medical status can range from “fit” to “frail,” which influences individual response to medications. Generally, age-related changes in the way their bodies metabolize drugs account for older patients’ increased sensitivity to drug side effects (Box).4-11
Atypical antipsychotics and dosages that have been shown benefit for managing behavioral symptoms in older patients with dementia include:
- risperidone, 0.5 to 1.5 mg/d12
- olanzapine, 5 to 10 mg/d13
- quetiapine, 25 to 350 mg/d14 (Table 2).15,16
Start with low dosages, and titrate slowly. Increase once or twice a week until the lowest effective dosage is reached.
Augmenting agents. If antipsychotic monotherapy fails to achieve an adequate response or if side effects limit dosing, adjunctive agents may be added with caution. Augmenting agents that have shown benefit in some patients with dementia include:
- mood stabilizers such as divalproex17 or carbamazepine18
- cholinesterase inhibitors, such as donepezil, rivastigmine, or galantamine.19
Start divalproex at 125 mg bid or carbamazepine at 100 mg bid and titrate to effect. Concomitant carbamazepine will decrease blood levels of risperidone, olanzapine, and quetiapine because of hepatic enzyme induction.20
Start donepezil at 5 mg once daily and increase after 4 to 6 weeks to 10 mg qd. When using rivastigmine, start with 1.5 mg bid and titrate to 9 to 12 mg/d in divided doses. Start galantamine at 4 mg bid and increase after 1 month to 8 mg bid.
Table 1
Suggested psychosocial interventions for older patients with dementia
Communicate clearly
|
Minimize the impact of sensory deficits
|
Modify environment when necessary
|
Encourage consistent daily routines
|
Optimize social/physical stimulation
|
Encourage caregiver to:
|
Antipsychotic side effects
Atypical antipsychotics are more effective than conventional agents in treating negative symptoms and are associated with lower rates of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD).21
Tardive dyskinesia. All antipsychotics can cause TD, although the risk is about 10 times greater with conventionals than atypicals. With conventionals, the annual cumulative TD incidence for young adults is 4 to 5%,22 and rates are much higher for middle-aged and older adults receiving chronic therapy:
- 29% after 1 year
- 50% after 2 years
- 63% after 3 years.23
In older patients, use atypical rather than conventional antipsychotics to minimize TD risk. Observe carefully; if TD symptoms occur, cautiously withdraw the antipsychotic and consider trying another agent.
Other risks. Atypical antipsychotics may cause sedation, orthostatic hypotension (with an increased risk for falls), increased serum prolactin, and weight gain (Table 2).
Weight gain from atypical antipsychotics has been associated with adverse effects on glucose metabolism and increased risk for type 2 diabetes.24 Some might argue that weight gain associated with olanzapine and other atypicals might benefit low-weight older patients. The frail elderly need to increase muscle mass, however, and the atypicals are associated with increases in fat mass.
Increased serum prolactin with risperidone theoretically could lead to loss of bone density, but evidence of this effect in older patients does not exist.
Start low, go slow
Clozapine may help control treatment-resistant psychosis in patients with schizophrenia and manage patients with severe TD.25 However, clozapine’s increased risk of agranulocytosis, neurologic side effects (seizures, sedation, confusion), and anticholinergic effects limit its use in older patients, particularly those with neurodegenerative disorders (Table 2).
Dosing. In rare cases when using clozapine in older patients, start with 6.25 to 12.5 mg/d. Increase by 6.25 to 12.5 mg once or twice a week to 50 to 100 mg/d.
Risperidone has been used to treat agitation in older patients with dementia in two small studies:
In a 9-week, open-label trial, 15 patients (mean age 78) with dementia were given risperidone, 0.5 to 3 mg/d. Agitation improved significantly, as measured by the Cohen-Mansfield Agitation Inventory (CMAI)—a 29-item questionnaire completed by caregivers.26 CMAI scores at study’s end averaged 49.5, compared with 70.5 at baseline.27
A 12-week, placebo-controlled, doubleblind study examined risperidone—0.5, 1, or 2 mg/d—in 625 institutionalized patients (mean age 83) with dementia and agitation. Ninety-six patients had Functional Assessment Staging Rating Scale scores of 6A, indicating moderate to severe dementia. In patients receiving risperidone, these behavioral measures were significantly reduced:
- Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) total scores, which measure behavior severity
- BEHAVE-AD psychosis subscale scores
- BEHAVE-AD aggressiveness scores
- CMAI verbal and aggression scores.
Adverse effects were reported at 82% for all three risperidone dosages and 85% for placebo. Side effects including somnolence, EPS, and peripheral edema were dose-related.12
Another trial compared risperidone or haloperidol, 0.5 to 4 mg/d, with placebo in treating 344 patients with behavioral symptoms of dementia. After 12 weeks of risperidone, mean dosage 1.1 mg/d:
- mean total BEHAVE-AD score decreased by 53%, compared with 37% in the placebo group
- CMAI score decreased by 32%, compared with 18% in the placebo group.
EPS were more severe with haloperidol than with risperidone or placebo.28
Risk of stroke. A small but significantly increased incidence of stroke and stroke-like events was recently reported in older patients with dementia when treated with risperidone. These events occurred in double-blind, placebocontrolled trials in patients (mean age 82) with Alzheimer’s, vascular, and mixed dementias.
Pharmacokinetic changes can influence concentrations of drugs in tissue compartments over time. Drug absorption declines with normal aging, but a clinically significant decrease in total absorption of psychotropics appears not to occur.13
In the liver, lipid-soluble psychotropics are metabolized into pharmacologically active or inactive metabolites. Some metabolic pathways, such as demethylation, may be influenced by age, leading to increased plasma concentrations of drugs and their metabolites.14,15 However, hydroxylation tends not to be affected by age.16
The ratio of body fat to water increases with aging,13 increasing the volume of distribution for lipid-soluble psychotropics. An age-related decrease in glomerular filtration accounts in part for increased accumulation of hydrophilic metabolites in some older patients.17,18
Pharmacodynamic changes with aging occur in neurotransmitter systems within cellular processing, such as at receptor or reuptake levels.19 These changes may exaggerate drug-drug interactions or affect complex neurotransmitter interactions.
The number of neurons in nigrostriatal pathways declines with age. Decreases are also seen in tyrosine hydroxylase activity, presynaptic dopamine D2 receptors, and dopamine levels—which may be particularly relevant to a discussion of antipsychotic medications.20
The net effect of these changes is the need to prescribe lower-than-usual starting and target dosages of many medications, including antipsychotics.
Most patients who experienced cerebrovascular events had one or more stroke risk factors, including diabetes, hypertension, atrial fibrillation, heart arrhythmia, atherosclerosis, or heart failure. They did not show a pattern of reduced blood pressure or orthostatic changes.12,29
Table 2
Antipsychotic side effects and dosages in older patients with dementia*
| Side effect | Clozapine (6.25 to 100 mg/d) | Risperidone (0.5 to 1.5 mg/d) | Olanzapine (5 to 10 mg/d) | Quetiapine (25 to 350 mg/d) |
|---|---|---|---|---|
| Orthostasis | ++++ | ++++ | +++ | ++ |
| Sedation | +++++ | ++ | +++ | ++ |
| Prolactin increase | 0 | +++ | + | 0 |
| Weight gain | ++++ | + | +++ | + |
| EPS | 0/+ | ++ | + | 0/+ |
| Tardive dyskinesia | 0 | + | + | ? |
| Anticholinergic effects | ++++ | + | + | 0 |
| Seizure risk | +++ | + | + | + |
| Hematologic effects | +++ | + | + | + |
| Source: Adapted from references 15 and 16. | ||||
| * Side-effect profiles and recommended dosages of ziprasidone and aripiprazole in older patients are not yet established. | ||||
| EPS: Extrapyramidal symptoms | ||||
| Key: | ||||
| 0 = none | ||||
| + = slight | ||||
| +++ = mild | ||||
| +++++ = marked | ||||
| 0/+ = none to slight | ||||
| ++ = very mild | ||||
| ++++ = moderate | ||||
Dosing. For older patients with dementia and psychosis, start risperidone at 0.25 to 0.5 mg/d and increase by no more than 0.25 to 0.5 mg once or twice per week. Do not exceed 3 mg/d. For agitation, a 1998 Expert Consensus Guideline Series panel2 recommended starting risperidone at 0.25 to 0.5 mg/d and increasing to an average of 0.5 to 1.5 mg/d.
Olanzapine. Two double-blind, placebo-controlled studies have examined olanzapine in treating agitation associated with dementia.
Saterlee et al30 compared olanzapine, mean 2.4 mg/d, with placebo in outpatients (mean age 79) with Alzheimer’s disease and psychosis. No significant differences were noted in hepatic transaminase levels, leukopenia, EPS, or orthostatic changes.
In a later study,13 nursing home patients (mean age 83) with Alzheimer’s disease, psychosis, and agitation were randomly assigned to receive olanzapine—5, 10, or 15 mg/d—or placebo. After 6 weeks, patients receiving olanzapine, 5 or 10 mg/d, showed significant improvement in Neuropsychiatric Inventory (NPI) total core scores. Olanzapine, 15 mg/d, was not significantly more effective than placebo.
Adverse events such as somnolence and abnormal gait occurred more often with olanzapine than placebo. The somnolence rate with olanzapine was 14% for 5 mg/d and 13% for 10 mg/d, compared with 3% for placebo. For abnormal gait, the rate with olanzapine was 11% for 5 mg/d and 7% for 10 mg/d, compared with 1% for placebo.
Dosing. Start olanzapine at 2.5 mg/d, and increase after 1 to 3 days to 5 mg/d. If symptoms are not adequately controlled, titrate by 2.5-mg increments to 10 mg/d.
Quetiapine. One open-label study14 examined using quetiapine in older patients with psychotic disorders. The study enrolled 184 patients (mean age 76) with Alzheimer’s disease, Parkinson’s disease, schizophrenia, vascular dementia, schizoaffective disorder, bipolar disorder, or major depression. Before the trial, patients were taking various conventional and atypical antipsychotics.
Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions (CGI) scores improved significantly after 52 weeks of quetiapine, median 137.5 mg/d. BPRS scores improved 20% in 49% of patients who completed the study.
Less than one-half (48%) of enrolled patients completed the study. Reasons for withdrawal included lack of efficacy (19%), adverse events or illness (15%; adverse events alone, 11%), lost to follow-up (13%), protocol noncompliance (3%), or diminished need for treatment (2%).
EPS occurred in 13% of patients. Mean total scores on the Simpson-Angus Rating Scale for Extrapyramidal Side Effects decreased 1.8 points, indicating reduced parkinsonian symptoms.
Dosing. Start quetiapine at 25 mg once at bedtime or bid; increase in 25-mg increments until the lowest effective dosage is achieved.
Ziprasidone. Little data exist on using ziprasidone in long-term care. In one recent study,31 ziprasidone (mean 100 mg/d) was given to 62 patients ages 64 to 92 with medical illnesses plus major depression, bipolar disorder, schizoaffective disorder, Alzheimer’s disease, or multi-infarct dementia. A retrospective chart review of 10 patients showed decreased agitation, as mean NPI scores declined from 76 to 33.
Sedation was the most common side effect. QTc findings, postural hypotension, and syncope rates did not change. Despite its limitations, this study suggests that ziprasidone is safe and effective in treating psychosis associated with dementia or other disorders.
Aripiprazole. As with ziprasidone, little data exist to guide the use of aripiprazole in older patients. In a randomized preliminary trial,32 192 noninstitutionalized patients with Alzheimer’s disease and psychosis were treated for 10 weeks with aripiprazole, mean 10 mg/d, or placebo.
At 8 and 10 weeks, BPRS psychosis subscale scores improved significantly in patients taking aripiprazole, compared with placebo. EPS and akathisia improved, and somnolence was the most common side effect. Although this study enrolled noninstitutionalized patients with dementia, the results suggest that aripiprazole may help treat long-term care residents with neurodegenerative disorders and behavioral disturbances.
Related resources
- Zaraa AS. Dementia update: Pharmacologic management of agitation and psychosis in older demented patients. Geriatrics 2003;58(10):48-53.
- Mills EJ, Chow TW. Randomized controlled trials in long-term care of residents with dementia: a systematic review. J Am Med Dir Assoc 2003;4(6):302-7.
- Alzheimer’s Association. Treating agitation. www.alz.org/PhysCare/Treating/agitation.htm
Drug brand names
- Aripiprazole • Abilify
- Carbamazepine • Tegretol
- Clozapine • Clozaril
- Donepezil • Aricept
- Galantamine • Reminyl
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Rivastigmine • Exelon
- Valproate • Depakote
- Ziprasidone • Geodon
Disclosure
Dr. Kasckow receives research support from, is a consultant to, or is a speaker for Eli Lilly & Co., Forest Laboratories, Solvay Pharmaceuticals, AstraZeneca Pharmaceuticals, Organon, Janssen Pharmaceutica, and Pfizer Inc.
Dr. Mulchahey reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Mohamed receives research support form Forest Laboratories and is a speaker for Eli Lilly & Co.
1. Finkel S, Costa e Silva J, Cohen G, et al. Behavioral and psychological symptoms of dementia: a consensus statement on current knowledge and implications for research and treatment. Am J Geriatr Psychiatry 1998;6:97-100.
2. The Expert Consensus Panel for Agitation in Dementia. Treatment of agitation in older persons with dementia. Postgrad Med 1998;4(suppl):1-88.
3. Cohen-Mansfield J. Nonpharmacologic interventions for inappropriate behaviors in dementia: a review, summary, and critique. Am J Geriatr Psychiatry 2001;9(4):361-81.
4. Davidson J. Pharmacologic treatment. In: Busse E, Blazer D (eds). Textbook of geriatric psychiatry (2nd ed). Washington DC: American Psychiatric Publishing, 1996:359-79.
5. Nies A, Robinson DS, Friedman MJ, et al. Relationship between age and tricyclic antidepressant plasma levels. Am J Psychiatry 1977;134(7):790-3.
6. Greenblatt DJ, Shader RJ. Benzodiazepine kinetics in the elderly. In: Usdin E (ed). Clinical pharmacology in psychiatry. New York: Elsevier, 1981;174-81.
7. Pollock BG, Perel JM, Altieri LP, et al. Debrisoquine hydroxylation phenotyping in geriatric psychopharmacology. Psychopharmacol Bull. 1992;28(2):163-8.
8. Nelson JC, Atillasoy E, Mazure C, Jatlow PI. Hydroxydesipramine in the elderly. J Clin Psychopharmacol 1988;8(6):428-33.
9. Young RC, Alexopoulos GS, Shamoian CA, et al. Plasma 10-hydroxynortriptyline in elderly depressed patients. Clin Pharmacol Ther 1984;35(4):540-4.
10. Cantillon M, Molchan SE, Little J. Pharmacological and neuroendocrine probes in neuropsychiatric illness. In: Coffey CE, Cummings JL (eds). Textbook of geriatric neuropsychiatry. Washington, DC: American Psychiatric Publishing, 1994.
11. Young RC, Meyers BS. Psychopharmacology. In: Sadovoy J, Lazarus LW, Jarvik LF, Grossberg GT (eds). Comprehensive review of geriatric psychiatry. Washington DC: American Psychiatric Publishing, 1996;755-817.
12. Katz IR, Jeste DV, Mintzer JE, et al. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. J Clin Psychiatry 1999;60(2):107-15.
13. Street JS, Clark WS, Gannon KS, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group. Arch Gen Psychiatry 2000;57(10):968-76.
14. Tariot PN, Salzman C, Yeung PP, et al. Long-term use of quetiapine in elderly patients with psychotic disorders. Clin Ther 2000;22(9):1068-84.
15. Casey DE. The relationship of pharmacology to side effects. J Clin Psychiatry 1997;58(suppl):55-62.
16. Pickar D. Prospects for pharmacotherapy of schizophrenia. Lancet 1995;345:557-62.
17. Kasckow JW, McElroy SL, Cameron RL, et al. A pilot study on the use of divalproex sodium in the treatment of behavioral agitation in elderly patients with dementia: assessment with the BEHAVE-AD and CGI rating scales. Curr Ther Res 1997;58(12):981-9.
18. Tariot PN, Erb R, Podgorski CA, et al. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry 1998;155(1):54-61.
19. Kasckow JW. Cognitive enhancers for dementia: do they work? Current Psychiatry 2002;1(3):22-8.
20. Lacy C, Armstrong L, Goldman M, Lance L. (eds) Lexicomp drug information handbook. Hudson, OH: Lexicomp, 2003-2004:1225-27, 1189-90, 1026-27.
21. Jeste DV, Lacro JP, Bailey A, et al. Lower incidence of tardive dyskinesia with risperidone compared with haloperidol in older patients. J Am Geriatr Soc 1999;47(6):716-19.
22. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45(9):789-96.
23. Jeste DV, Caligiuri MP, Paulsen JS, et al. Risk of tardive dyskinesia in older patients. A prospective longitudinal study of 266 outpatients. Arch Gen Psychiatry 1995;52(9):756-65.
24. Sernyak MJ, Leslie DL, Alarcon RD, et al. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002;159:561-6.
25. Chengappa KN, Baker RW, Kreinbrook SB, Adair D. Clozapine use in female geriatric patients with psychoses. JGeriatr Psychiatry Neurol 1995;8(1):12-15.
26. Cohen-Mansfield J, Marx MS, Rosenthal AS. A description of agitation in the nursing home. J Gerontol 1989;44(3):M77-84.
27. Lavretsky H, Sultzer D. A structured trial of risperidone for the treatment of agitation in dementia. Am J Geriatr Psychiatry 1998;6(2):127-35.
28. De Deyn PP, Rabheru K, Rasmussen A, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999;53(5):946-55.
29. Brodaty H, Ames D, Snowdon J, et al. A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia. J Clin Psychiatry 2003;64(2):134-43.
30. Satterlee W, Reams SG, Burns PR, et al. A clinical update on olanzapine treatment in schizophrenia and in elderly Alzheimer’s disease patients (abstract). Psychopharmacol Bull 1995;31:534.-
31. Berkowitz A. Ziprasidone for elderly dementia: a case series (abstract). San Francisco, CA: American Psychiatric Association annual meeting, 2003.
32. De Deyn PP, Jeste D, Auby P, Carson W. Aripiprazole in dementia of the Alzheimer’s type (abstract). Honolulu, HI: American Association for Geriatric Psychiatry annual meeting, 2003.
1. Finkel S, Costa e Silva J, Cohen G, et al. Behavioral and psychological symptoms of dementia: a consensus statement on current knowledge and implications for research and treatment. Am J Geriatr Psychiatry 1998;6:97-100.
2. The Expert Consensus Panel for Agitation in Dementia. Treatment of agitation in older persons with dementia. Postgrad Med 1998;4(suppl):1-88.
3. Cohen-Mansfield J. Nonpharmacologic interventions for inappropriate behaviors in dementia: a review, summary, and critique. Am J Geriatr Psychiatry 2001;9(4):361-81.
4. Davidson J. Pharmacologic treatment. In: Busse E, Blazer D (eds). Textbook of geriatric psychiatry (2nd ed). Washington DC: American Psychiatric Publishing, 1996:359-79.
5. Nies A, Robinson DS, Friedman MJ, et al. Relationship between age and tricyclic antidepressant plasma levels. Am J Psychiatry 1977;134(7):790-3.
6. Greenblatt DJ, Shader RJ. Benzodiazepine kinetics in the elderly. In: Usdin E (ed). Clinical pharmacology in psychiatry. New York: Elsevier, 1981;174-81.
7. Pollock BG, Perel JM, Altieri LP, et al. Debrisoquine hydroxylation phenotyping in geriatric psychopharmacology. Psychopharmacol Bull. 1992;28(2):163-8.
8. Nelson JC, Atillasoy E, Mazure C, Jatlow PI. Hydroxydesipramine in the elderly. J Clin Psychopharmacol 1988;8(6):428-33.
9. Young RC, Alexopoulos GS, Shamoian CA, et al. Plasma 10-hydroxynortriptyline in elderly depressed patients. Clin Pharmacol Ther 1984;35(4):540-4.
10. Cantillon M, Molchan SE, Little J. Pharmacological and neuroendocrine probes in neuropsychiatric illness. In: Coffey CE, Cummings JL (eds). Textbook of geriatric neuropsychiatry. Washington, DC: American Psychiatric Publishing, 1994.
11. Young RC, Meyers BS. Psychopharmacology. In: Sadovoy J, Lazarus LW, Jarvik LF, Grossberg GT (eds). Comprehensive review of geriatric psychiatry. Washington DC: American Psychiatric Publishing, 1996;755-817.
12. Katz IR, Jeste DV, Mintzer JE, et al. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. J Clin Psychiatry 1999;60(2):107-15.
13. Street JS, Clark WS, Gannon KS, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group. Arch Gen Psychiatry 2000;57(10):968-76.
14. Tariot PN, Salzman C, Yeung PP, et al. Long-term use of quetiapine in elderly patients with psychotic disorders. Clin Ther 2000;22(9):1068-84.
15. Casey DE. The relationship of pharmacology to side effects. J Clin Psychiatry 1997;58(suppl):55-62.
16. Pickar D. Prospects for pharmacotherapy of schizophrenia. Lancet 1995;345:557-62.
17. Kasckow JW, McElroy SL, Cameron RL, et al. A pilot study on the use of divalproex sodium in the treatment of behavioral agitation in elderly patients with dementia: assessment with the BEHAVE-AD and CGI rating scales. Curr Ther Res 1997;58(12):981-9.
18. Tariot PN, Erb R, Podgorski CA, et al. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry 1998;155(1):54-61.
19. Kasckow JW. Cognitive enhancers for dementia: do they work? Current Psychiatry 2002;1(3):22-8.
20. Lacy C, Armstrong L, Goldman M, Lance L. (eds) Lexicomp drug information handbook. Hudson, OH: Lexicomp, 2003-2004:1225-27, 1189-90, 1026-27.
21. Jeste DV, Lacro JP, Bailey A, et al. Lower incidence of tardive dyskinesia with risperidone compared with haloperidol in older patients. J Am Geriatr Soc 1999;47(6):716-19.
22. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45(9):789-96.
23. Jeste DV, Caligiuri MP, Paulsen JS, et al. Risk of tardive dyskinesia in older patients. A prospective longitudinal study of 266 outpatients. Arch Gen Psychiatry 1995;52(9):756-65.
24. Sernyak MJ, Leslie DL, Alarcon RD, et al. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002;159:561-6.
25. Chengappa KN, Baker RW, Kreinbrook SB, Adair D. Clozapine use in female geriatric patients with psychoses. JGeriatr Psychiatry Neurol 1995;8(1):12-15.
26. Cohen-Mansfield J, Marx MS, Rosenthal AS. A description of agitation in the nursing home. J Gerontol 1989;44(3):M77-84.
27. Lavretsky H, Sultzer D. A structured trial of risperidone for the treatment of agitation in dementia. Am J Geriatr Psychiatry 1998;6(2):127-35.
28. De Deyn PP, Rabheru K, Rasmussen A, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999;53(5):946-55.
29. Brodaty H, Ames D, Snowdon J, et al. A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia. J Clin Psychiatry 2003;64(2):134-43.
30. Satterlee W, Reams SG, Burns PR, et al. A clinical update on olanzapine treatment in schizophrenia and in elderly Alzheimer’s disease patients (abstract). Psychopharmacol Bull 1995;31:534.-
31. Berkowitz A. Ziprasidone for elderly dementia: a case series (abstract). San Francisco, CA: American Psychiatric Association annual meeting, 2003.
32. De Deyn PP, Jeste D, Auby P, Carson W. Aripiprazole in dementia of the Alzheimer’s type (abstract). Honolulu, HI: American Association for Geriatric Psychiatry annual meeting, 2003.
When and how to use SSRIs to treat late-life depression
Despite its impact on individuals and public health, depression in older persons is inadequately diagnosed and treated. Even when depression is diagnosed, only one-third of persons older than 65 receive treatment.1 Reasons for this include:
- lack of physician awareness that depression presents differently in older than in younger adults
- patient denial of depressive symptoms
- patients’ and physicians’ mistaken belief that feeling depressed is a normal part of aging.
The good news is that when geriatric depression is recognized, it usually responds favorably to treatment, although aggressive intervention may be required.2 In this article, we describe our approach to diagnosis and discuss use of selective serotonin reuptake inhibitors (SSRIs) as first-line antidepressants for older patients.
Late-life depression risk factors
Depression is common in older persons, especially in those who have experienced psychosocial or medical losses, including chronic illness. Although its presentation often does not meet criteria for major depression, the more common subsyndromal depression is debilitating and can lead to suicide.
A 72-year-old man presents with trouble concentrating, decreased appetite, anergy, and anhedonia. He says he frequently awakes at 3 AM, and it takes him 2 hours to return to sleep. Lately, he has thought of shooting himself with his hunting rifle. The patient’s wife died of cancer 1 year ago, and he has developed several medical illnesses within the past 10 years: chronic obstructive pulmonary disease, worsening arthritis, mild ischemic heart disease, and worsening hearing loss.
The patient denies feeling depressed and instead attributes his symptoms to his medical illnesses. He has become progressively isolated in the past year, with less social contact with his friends at the local parish. His older brother, with whom he was close, died recently. Until now, he says his “pride” has made him resist his primary care physician’s recommendation that he see a psychiatrist.
Late-life depressive syndromes commonly present with somatic complaints. Typically, patients deny having a mental illness and perceive that their symptoms are organic in origin (Box).1
Losses. Psychosocial and medical losses are major risk factors for late-life adjustment disorders, subsyndromal depressive disorders, and major depression. Medical losses may include loss of mobility or independent function, chronic pain, or sensory losses that limit one’s ability to read or hear. Psychosocial losses may include the death of a spouse, sibling, or peer or moving from one’s longtime home to a more structured environment (assisted living, nursing home, or living with relatives).
Medical causes to rule out before starting antidepressant therapy include:
- hypothyroidism
- medication side effects
- bipolar disorder, which may require the use of a mood-stabilizing agent to prevent manic symptoms.3
History. Often a history of mood disorder in the individual or a family member can help the clinician determine that mental illness accounts for the patient’s symptoms. In older patients, it is not uncommon for psychotic symptoms to accompany a primary mood disturbance.
Suicide risk is high in depressed older persons, so detection and quick treatment of depression is paramount. Older white men are at particularly high risk for completed suicide using firearms.3
Alcohol abuse may contribute to depressive symptoms in older persons. A second peak of alcoholism occurs in the eighth decade of life and can confound diagnosis of depression in patients of this age.
Making the diagnosis. In patients who present with symptoms and risk factors for late-life depression, depression rating scales can help confirm the diagnosis. Commonly used scales include the Beck Depression Inventory, the Hamilton Depression Rating Scale, and the Zung Self-Rating Depression Scale. Specialized scales for use in older patients include the Geriatric Depression Scale and the Cornell Scale; the latter scale is designed for patients with comorbid depression and dementia.3,4
Treatment
Antidepressant treatment in combination with psychotherapy usually is warranted when treating nonpsychotic late-life depression. In patients with psychosis, electroconvulsive therapy can help achieve remission.
Cognitive-behavioral therapy and interpersonal and insight-oriented psychotherapy have been shown to be effective in late-life depression. Social interventions aimed at preventing isolation also can work. In milder cases of depression, psychotherapy alone may be sufficient.3
Starting dosages. When antidepressant therapy is indicated in an older patient, start low and go slow.5 Older patients generally require prolonged titration rates and a longer course of treatment than do younger patients. Physiologic changes that occur with aging include:
- altered drug metabolism rate, including slower demethylation
- increased body fat-to-water ratio, which increases the volume of distribution for lipophilic psychotropic drugs
- decreased glomerular filtration rate, which may account for higher serum concentrations of drugs and their metabolites
- increased sensitivity of the older brain to the effects of medications.6
Thus—with some exceptions—recommended starting dosages for older patients are usually one-half those used in younger adults. For the frail older patient, the starting dosage should probably be even lower—about one-fourth the typical starting dosage in young adults.6 As in younger patients, the treatment goal is to achieve the maximal therapeutic effect with the lowest effective dosage while avoiding side effects.
More time may be required to achieve a therapeutic effect in older than in younger patients. Substantial improvement may not be seen until an older patient has been taking an antidepressant for 9 weeks or longer. In younger patients, responses are seen as early as 2 weeks after starting antidepressant therapy, and remission occurs within 6 to 8 weeks.2
SSRIs versus tricyclics
SSRIs—citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline (Table 1)7 —are considered first-line antidepressants for late-life depression. Although SSRIs and tricyclic antidepressants (TCAs) demonstrate equivalent efficacy in older adults, SSRIs are associated with lesstroublesome side effects.2
SSRIs are less sedating than tricyclics and are not associated with adverse effects on cognition; both qualities make these agents appropriate for older patients. Risk of overdose with SSRIs also is much lower than with TCAs.2
Both types of agent have been reported to cause movement disorders such as extrapyramidal symptoms and even tardive dyskinesia, but these side effects are much more rare with SSRIs than with TCAs.2 Also—unlike the TCAs— SSRIs do not significantly effect cardiac conduction, which is an important quality in the older population with its relatively high incidence of heart disease.
Table 1
USING SSRIs TO TREAT LATE-LIFE DEPRESSION
| Drug | Half-life (hours)* | Recommended dosage after age 65 (mg/d) † |
|---|---|---|
| Citalopram | 35 | 20 to 40 |
| Escitalopram | 27 - 32 | 10 to 20 |
| Fluoxetine | 96 - 386 | 10 to 60 |
| Fluvoxamine | 16 | 25 to 300 |
| Paroxetine | 21 | 10 to 40 |
| Sertraline | 26 | 25 to 200 |
| * In the older patient, medication half-lives may be extended 1.5to 2-fold. | ||
| † The heterogeneity of aging can lead to a wide variation in antidepressant target dosages. Therefore, although starting dosages for older adults are lower, final dosages may be the same as for younger adults. | ||
| Source: Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics Co, 2002. | ||
Meta-analyses suggest that patients are more likely to discontinue taking tricyclics than SSRIs.8 Adherence to antidepressant medications by older patients has been associated with lower perceived stigma of mental illness, higher self-rated severity of illness, age over 60, and absence of a personality disorder.9
SSRI side effects
The most common side effect of SSRIs is nausea, which is usually mild and occurs in the first weeks of treatment.2 Dry mouth is related to noradrenergic influences on the salivary gland. Anxiety is usually transient.
Sedation can be a problem in older patients who use SSRIs. Among the six SSRIs indicated for depression, paroxetine appears to be the most sedating.10 Paroxetine exhibits the most muscarinic blockade in vitro, with a binding affinity less than that of imipramine but greater than nortriptyline.11 Studies in older patients have suggested, however, that cognitive function is not compromised with paroxetine, as is observed with other antidepressants with anticholinergic action.6
Table 2
CYTOCHROME P450 ISOZYMES INHIBITED BY SSRI ANTIDEPRESSANTS (IN VITRO)
| Drug | 1A2 | 2C9 | 2C19 | 2D6 | 3A4 |
|---|---|---|---|---|---|
| Fluoxetine | + | ++ | + | +++ | ++ |
| Sertraline | + | + | + | + | + |
| Paroxetine | + | + | + | +++ | + |
| Citalopram | + | ○ | ○ | + | ○ |
| Escitalopram | ○ | ○ | ○ | ○ | ○ |
| Fluvoxamine | +++ | ++ | +++ | + | ++ |
| Source: Adapted from Greenblatt et al. J Clin Psychiatry 1998;59(suppl 15):19-27, and von Moltke et al. Drug Metab Dispos 2001;29:1102-9. | |||||
Sexual function can be diminished by SSRIs; the most common sexual side effects are anorgasmia and delayed orgasm.12 Preserving sexual function is important to many older men and women who retain their interest in sexual activity well into later life.
Withdrawal syndrome. Abrupt discontinuation of some SSRIs can lead to withdrawal side effects, such as dizziness, fatigue, and nausea. In a study of young and older adults, withdrawal syndrome followed abrupt discontinuation at rates of 14% with fluoxetine and 60% with sertraline or paroxetine.13
Elimination half-life. Medication half-lives tend to be prolonged in older patients because of age-related pharmacokinetic changes. SSRIs with relatively shorter half-lives—such as citalopram, sertraline, paroxetine, and fluvoxamine—could be eliminated fairly rapidly should adverse events arise.
On the other hand, use of a longer-acting agent, such as fluoxetine, may be an advantage if compliance is a problem. In this case, fluoxetine’s prolonged washout rate could help protect a patient from relapse, even when doses are missed.
Potential drug-drug interactions
Individual SSRIs have different effects on the cytochrome P450 system (Table 2).14,15 For example, fluoxetine, sertraline, and paroxetine—but not fluvoxamine—are in vitro inhibitors of the 2D6 isoenzyme system,16 which metabolizes TCAs, type Ic antiarrhythmics, alpha-adrenergic blockers, dextromethorphan, chemotherapeutic agents, and some antipsychotics. Citalopram has minimal inhibitory activity and escitalopram has virtually no inhibitory action on CYP 2D6.17
Cytochrome P450 3A4 metabolizes numerous drugs, including alprazolam, triazolam, carbamazepine, calcium channel blockers, and others. The 3A4 enzymes are inhibited by fluoxetine, sertraline, and fluvoxamine.18
Cytochrome P450 1A2 is the liver isoenzyme responsible for dealkylating theophylline, caffeine, and phenacetin. This enzyme system also metabolizes tacrine and clozapine. Of the SSRIs, fluvoxamine is the most potent inhibitor of the 1A2 enzyme, while escitalopram is a negligible inhibitor.17
Cytochrome P450 2C is a subfamily of isoenzymes that includes 2C9, 2C10, 2C19, and others. This system metabolizes some antidepressants as well as warfarin, phenytoin, and diazepam. Inhibitors of this system include fluvoxamine, fluoxetine, sertraline, and paroxetine.18
MAO inhibitors. Concomitant use of serotonin-acting drugs and monoamine oxidase inhibitors should be avoided. When used in combination, SSRIs and MAO inhibitors can cause a serotonin syndrome, with potential hyperpyretic crises, seizures, coma, and death. When switching medications, it is important to eliminate any serotonin-acting drug before starting an MAO inhibitor.2
In young adults, a 7-day washout is needed when switching from fluvoxamine and 14 days when switching from sertraline, citalopram, or paroxetine. With fluoxetine, the washout period is 35 days in young adults. Because medication half-lives in older patients may be prolonged two- to three-fold, it is advisable to proceed conservatively and extend these washout periods accordingly.
Related resources
- National Institute of Mental Health. Older adults: Depression and suicide facts. www.nimh.nih.gov/publicat/elderlydepsuicide.cfm
- WebMD Health/depression. http://my.webmd.com/condition_center/dep
- Salzman C, Wong E, Wright BC. Drug and ECT treatment of depression in the elderly, 1996-2001: a literature review. Biol Psychiatry 2002;52(3):265-84.
Drug brand names
- Alprazolam • Xanax
- Citalopram • Celexa
- Clozapine • Clozaril
- Diazepam • Valium
- Escitalopram • Lexapro
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Paroxetine • Paxil
- Sertraline • Zoloft
- Tacrine • Cognex
- Triazolam • Halcion
Disclosure
Dr. Kasckow reports that he receives grant/research support from, serves as a consultant to, or is on the speakers bureau of Eli Lilly and Co., Forest Laboratories, Pharmacia Corp., Solvay Pharmaceuticals, AstraZeneca Pharmaceuticals, Organon, Janssen Pharmaceutica, and Pfizer Inc.
Dr. Mohamed reports that she receives grant/research support from Forest Laboratories and serves on the speakers bureau of Eli Lilly and Co.
Dr. Herman reports that he serves as a consultant to Eli Lilly and Co.
Other co-authors report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
1. Judd LL, Paulus MP, Wells KB, Rapaport MH. Socioeconomic burden of subsyndromal depressive symptoms and major depression in a sample of the general population. Am J Psychiatry 1996;153:1411-7.
2. Mulchahey JJ, Malik MS, Sabai M, Kasckow JW. Serotonin selective reuptake inhibitors in the treatment of geriatric depression and related disorders. Int J Neuropsychopharmacol 1999;2:121-7.
3. Blazer DG, Koenig HG. Mood disorders. In: Busse EW, Blazer DG (eds). Textbook of geriatric psychiatry (2nd ed). Washington, DC: American Psychiatric Press, 1996;235-63.
4. Blazer DG. The psychiatric interview of the geriatric patient. In: Busse EW, Blazer DG (eds). Textbook of geriatric psychiatry (2nd ed). Washington, DC: American Psychiatric Press, 1996;175-89.
5. Young RC, Meyers BS. Psychopharmacology. In: Sadovoy J, Lazarus LW, Jarvik LF, Grossberg GP (eds). Comprehensive review of geriatric psychiatry, vol. II. Washington, DC: American Psychiatric Publishing, 1996;755:817.-
6. Dunner DL. Therapeutic considerations in treating depression in the elderly. J Clin Psychiatry 1994;55(suppl):48-58.
7. Physicians’ desk reference (56th ed). Montvale, NJ: Medical Economics Co, 2002.
8. Montgomery SA, Henry J, McDonald G, et al. Selective serotonin reuptake inhibitors: meta-analysis of discontinuation rates. Int Clin Psychopharmacol 1994;9:47-53.
9. Sirey JA, Bruce ML, Alexopoulos GS, Perlick DA, Friedman SJ, Meyers BS. Stigma as a barrier to recovery. Perceived stigma and patient-rated severity of illness as predictors of antidepressant drug adherence. Psychiatry Serv 2001;52:1615-20.
10. Dechant KL, Clissold SP. Paroxetine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in depressive illness Drugs 1991;41:225-53.
11. Richelson E. Pharmacology of antidepressants: characteristics of the ideal drug. Mayo Clin Proc 1994;69:1069-81.
12. Herman JB, Brotman AW, Pollack MH, Falk WE, Biederman J, Rosenbaum JF. Fluoxetine-induced sexual dysfunction. J Clin Psychiatry 1990;51:25-7.
13. Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998;44:77-87.
14. Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI. Drug interactions with newer antidepressants: role of human cytochromes P450. J Clin Psychiatry 1998;59(suppl 15):19-27.
15. von Moltke LL, Greenblatt DJ, Giancarlo GM, Granda BW, Harmatz JS, Shader RI. Escitalopram (s-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to r-citalopram. Drug Metab Dispos 2001;29:1102-9.
16. Nemeroff CB, DeVane CL, Pollock BG. Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996;153:311-20.
17. Owens MJ, Rosenbaum JF. Escitalopram: a second-generation SSRI. CNS Spectrums 2002;7(suppl 1):4.-
18. Preskorn SH. Recent pharmacologic advances in antidepressant therapy for the elderly. Am J Med 1993;94(suppl 5A):2S-12S.
Despite its impact on individuals and public health, depression in older persons is inadequately diagnosed and treated. Even when depression is diagnosed, only one-third of persons older than 65 receive treatment.1 Reasons for this include:
- lack of physician awareness that depression presents differently in older than in younger adults
- patient denial of depressive symptoms
- patients’ and physicians’ mistaken belief that feeling depressed is a normal part of aging.
The good news is that when geriatric depression is recognized, it usually responds favorably to treatment, although aggressive intervention may be required.2 In this article, we describe our approach to diagnosis and discuss use of selective serotonin reuptake inhibitors (SSRIs) as first-line antidepressants for older patients.
Late-life depression risk factors
Depression is common in older persons, especially in those who have experienced psychosocial or medical losses, including chronic illness. Although its presentation often does not meet criteria for major depression, the more common subsyndromal depression is debilitating and can lead to suicide.
A 72-year-old man presents with trouble concentrating, decreased appetite, anergy, and anhedonia. He says he frequently awakes at 3 AM, and it takes him 2 hours to return to sleep. Lately, he has thought of shooting himself with his hunting rifle. The patient’s wife died of cancer 1 year ago, and he has developed several medical illnesses within the past 10 years: chronic obstructive pulmonary disease, worsening arthritis, mild ischemic heart disease, and worsening hearing loss.
The patient denies feeling depressed and instead attributes his symptoms to his medical illnesses. He has become progressively isolated in the past year, with less social contact with his friends at the local parish. His older brother, with whom he was close, died recently. Until now, he says his “pride” has made him resist his primary care physician’s recommendation that he see a psychiatrist.
Late-life depressive syndromes commonly present with somatic complaints. Typically, patients deny having a mental illness and perceive that their symptoms are organic in origin (Box).1
Losses. Psychosocial and medical losses are major risk factors for late-life adjustment disorders, subsyndromal depressive disorders, and major depression. Medical losses may include loss of mobility or independent function, chronic pain, or sensory losses that limit one’s ability to read or hear. Psychosocial losses may include the death of a spouse, sibling, or peer or moving from one’s longtime home to a more structured environment (assisted living, nursing home, or living with relatives).
Medical causes to rule out before starting antidepressant therapy include:
- hypothyroidism
- medication side effects
- bipolar disorder, which may require the use of a mood-stabilizing agent to prevent manic symptoms.3
History. Often a history of mood disorder in the individual or a family member can help the clinician determine that mental illness accounts for the patient’s symptoms. In older patients, it is not uncommon for psychotic symptoms to accompany a primary mood disturbance.
Suicide risk is high in depressed older persons, so detection and quick treatment of depression is paramount. Older white men are at particularly high risk for completed suicide using firearms.3
Alcohol abuse may contribute to depressive symptoms in older persons. A second peak of alcoholism occurs in the eighth decade of life and can confound diagnosis of depression in patients of this age.
Making the diagnosis. In patients who present with symptoms and risk factors for late-life depression, depression rating scales can help confirm the diagnosis. Commonly used scales include the Beck Depression Inventory, the Hamilton Depression Rating Scale, and the Zung Self-Rating Depression Scale. Specialized scales for use in older patients include the Geriatric Depression Scale and the Cornell Scale; the latter scale is designed for patients with comorbid depression and dementia.3,4
Treatment
Antidepressant treatment in combination with psychotherapy usually is warranted when treating nonpsychotic late-life depression. In patients with psychosis, electroconvulsive therapy can help achieve remission.
Cognitive-behavioral therapy and interpersonal and insight-oriented psychotherapy have been shown to be effective in late-life depression. Social interventions aimed at preventing isolation also can work. In milder cases of depression, psychotherapy alone may be sufficient.3
Starting dosages. When antidepressant therapy is indicated in an older patient, start low and go slow.5 Older patients generally require prolonged titration rates and a longer course of treatment than do younger patients. Physiologic changes that occur with aging include:
- altered drug metabolism rate, including slower demethylation
- increased body fat-to-water ratio, which increases the volume of distribution for lipophilic psychotropic drugs
- decreased glomerular filtration rate, which may account for higher serum concentrations of drugs and their metabolites
- increased sensitivity of the older brain to the effects of medications.6
Thus—with some exceptions—recommended starting dosages for older patients are usually one-half those used in younger adults. For the frail older patient, the starting dosage should probably be even lower—about one-fourth the typical starting dosage in young adults.6 As in younger patients, the treatment goal is to achieve the maximal therapeutic effect with the lowest effective dosage while avoiding side effects.
More time may be required to achieve a therapeutic effect in older than in younger patients. Substantial improvement may not be seen until an older patient has been taking an antidepressant for 9 weeks or longer. In younger patients, responses are seen as early as 2 weeks after starting antidepressant therapy, and remission occurs within 6 to 8 weeks.2
SSRIs versus tricyclics
SSRIs—citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline (Table 1)7 —are considered first-line antidepressants for late-life depression. Although SSRIs and tricyclic antidepressants (TCAs) demonstrate equivalent efficacy in older adults, SSRIs are associated with lesstroublesome side effects.2
SSRIs are less sedating than tricyclics and are not associated with adverse effects on cognition; both qualities make these agents appropriate for older patients. Risk of overdose with SSRIs also is much lower than with TCAs.2
Both types of agent have been reported to cause movement disorders such as extrapyramidal symptoms and even tardive dyskinesia, but these side effects are much more rare with SSRIs than with TCAs.2 Also—unlike the TCAs— SSRIs do not significantly effect cardiac conduction, which is an important quality in the older population with its relatively high incidence of heart disease.
Table 1
USING SSRIs TO TREAT LATE-LIFE DEPRESSION
| Drug | Half-life (hours)* | Recommended dosage after age 65 (mg/d) † |
|---|---|---|
| Citalopram | 35 | 20 to 40 |
| Escitalopram | 27 - 32 | 10 to 20 |
| Fluoxetine | 96 - 386 | 10 to 60 |
| Fluvoxamine | 16 | 25 to 300 |
| Paroxetine | 21 | 10 to 40 |
| Sertraline | 26 | 25 to 200 |
| * In the older patient, medication half-lives may be extended 1.5to 2-fold. | ||
| † The heterogeneity of aging can lead to a wide variation in antidepressant target dosages. Therefore, although starting dosages for older adults are lower, final dosages may be the same as for younger adults. | ||
| Source: Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics Co, 2002. | ||
Meta-analyses suggest that patients are more likely to discontinue taking tricyclics than SSRIs.8 Adherence to antidepressant medications by older patients has been associated with lower perceived stigma of mental illness, higher self-rated severity of illness, age over 60, and absence of a personality disorder.9
SSRI side effects
The most common side effect of SSRIs is nausea, which is usually mild and occurs in the first weeks of treatment.2 Dry mouth is related to noradrenergic influences on the salivary gland. Anxiety is usually transient.
Sedation can be a problem in older patients who use SSRIs. Among the six SSRIs indicated for depression, paroxetine appears to be the most sedating.10 Paroxetine exhibits the most muscarinic blockade in vitro, with a binding affinity less than that of imipramine but greater than nortriptyline.11 Studies in older patients have suggested, however, that cognitive function is not compromised with paroxetine, as is observed with other antidepressants with anticholinergic action.6
Table 2
CYTOCHROME P450 ISOZYMES INHIBITED BY SSRI ANTIDEPRESSANTS (IN VITRO)
| Drug | 1A2 | 2C9 | 2C19 | 2D6 | 3A4 |
|---|---|---|---|---|---|
| Fluoxetine | + | ++ | + | +++ | ++ |
| Sertraline | + | + | + | + | + |
| Paroxetine | + | + | + | +++ | + |
| Citalopram | + | ○ | ○ | + | ○ |
| Escitalopram | ○ | ○ | ○ | ○ | ○ |
| Fluvoxamine | +++ | ++ | +++ | + | ++ |
| Source: Adapted from Greenblatt et al. J Clin Psychiatry 1998;59(suppl 15):19-27, and von Moltke et al. Drug Metab Dispos 2001;29:1102-9. | |||||
Sexual function can be diminished by SSRIs; the most common sexual side effects are anorgasmia and delayed orgasm.12 Preserving sexual function is important to many older men and women who retain their interest in sexual activity well into later life.
Withdrawal syndrome. Abrupt discontinuation of some SSRIs can lead to withdrawal side effects, such as dizziness, fatigue, and nausea. In a study of young and older adults, withdrawal syndrome followed abrupt discontinuation at rates of 14% with fluoxetine and 60% with sertraline or paroxetine.13
Elimination half-life. Medication half-lives tend to be prolonged in older patients because of age-related pharmacokinetic changes. SSRIs with relatively shorter half-lives—such as citalopram, sertraline, paroxetine, and fluvoxamine—could be eliminated fairly rapidly should adverse events arise.
On the other hand, use of a longer-acting agent, such as fluoxetine, may be an advantage if compliance is a problem. In this case, fluoxetine’s prolonged washout rate could help protect a patient from relapse, even when doses are missed.
Potential drug-drug interactions
Individual SSRIs have different effects on the cytochrome P450 system (Table 2).14,15 For example, fluoxetine, sertraline, and paroxetine—but not fluvoxamine—are in vitro inhibitors of the 2D6 isoenzyme system,16 which metabolizes TCAs, type Ic antiarrhythmics, alpha-adrenergic blockers, dextromethorphan, chemotherapeutic agents, and some antipsychotics. Citalopram has minimal inhibitory activity and escitalopram has virtually no inhibitory action on CYP 2D6.17
Cytochrome P450 3A4 metabolizes numerous drugs, including alprazolam, triazolam, carbamazepine, calcium channel blockers, and others. The 3A4 enzymes are inhibited by fluoxetine, sertraline, and fluvoxamine.18
Cytochrome P450 1A2 is the liver isoenzyme responsible for dealkylating theophylline, caffeine, and phenacetin. This enzyme system also metabolizes tacrine and clozapine. Of the SSRIs, fluvoxamine is the most potent inhibitor of the 1A2 enzyme, while escitalopram is a negligible inhibitor.17
Cytochrome P450 2C is a subfamily of isoenzymes that includes 2C9, 2C10, 2C19, and others. This system metabolizes some antidepressants as well as warfarin, phenytoin, and diazepam. Inhibitors of this system include fluvoxamine, fluoxetine, sertraline, and paroxetine.18
MAO inhibitors. Concomitant use of serotonin-acting drugs and monoamine oxidase inhibitors should be avoided. When used in combination, SSRIs and MAO inhibitors can cause a serotonin syndrome, with potential hyperpyretic crises, seizures, coma, and death. When switching medications, it is important to eliminate any serotonin-acting drug before starting an MAO inhibitor.2
In young adults, a 7-day washout is needed when switching from fluvoxamine and 14 days when switching from sertraline, citalopram, or paroxetine. With fluoxetine, the washout period is 35 days in young adults. Because medication half-lives in older patients may be prolonged two- to three-fold, it is advisable to proceed conservatively and extend these washout periods accordingly.
Related resources
- National Institute of Mental Health. Older adults: Depression and suicide facts. www.nimh.nih.gov/publicat/elderlydepsuicide.cfm
- WebMD Health/depression. http://my.webmd.com/condition_center/dep
- Salzman C, Wong E, Wright BC. Drug and ECT treatment of depression in the elderly, 1996-2001: a literature review. Biol Psychiatry 2002;52(3):265-84.
Drug brand names
- Alprazolam • Xanax
- Citalopram • Celexa
- Clozapine • Clozaril
- Diazepam • Valium
- Escitalopram • Lexapro
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Paroxetine • Paxil
- Sertraline • Zoloft
- Tacrine • Cognex
- Triazolam • Halcion
Disclosure
Dr. Kasckow reports that he receives grant/research support from, serves as a consultant to, or is on the speakers bureau of Eli Lilly and Co., Forest Laboratories, Pharmacia Corp., Solvay Pharmaceuticals, AstraZeneca Pharmaceuticals, Organon, Janssen Pharmaceutica, and Pfizer Inc.
Dr. Mohamed reports that she receives grant/research support from Forest Laboratories and serves on the speakers bureau of Eli Lilly and Co.
Dr. Herman reports that he serves as a consultant to Eli Lilly and Co.
Other co-authors report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
Despite its impact on individuals and public health, depression in older persons is inadequately diagnosed and treated. Even when depression is diagnosed, only one-third of persons older than 65 receive treatment.1 Reasons for this include:
- lack of physician awareness that depression presents differently in older than in younger adults
- patient denial of depressive symptoms
- patients’ and physicians’ mistaken belief that feeling depressed is a normal part of aging.
The good news is that when geriatric depression is recognized, it usually responds favorably to treatment, although aggressive intervention may be required.2 In this article, we describe our approach to diagnosis and discuss use of selective serotonin reuptake inhibitors (SSRIs) as first-line antidepressants for older patients.
Late-life depression risk factors
Depression is common in older persons, especially in those who have experienced psychosocial or medical losses, including chronic illness. Although its presentation often does not meet criteria for major depression, the more common subsyndromal depression is debilitating and can lead to suicide.
A 72-year-old man presents with trouble concentrating, decreased appetite, anergy, and anhedonia. He says he frequently awakes at 3 AM, and it takes him 2 hours to return to sleep. Lately, he has thought of shooting himself with his hunting rifle. The patient’s wife died of cancer 1 year ago, and he has developed several medical illnesses within the past 10 years: chronic obstructive pulmonary disease, worsening arthritis, mild ischemic heart disease, and worsening hearing loss.
The patient denies feeling depressed and instead attributes his symptoms to his medical illnesses. He has become progressively isolated in the past year, with less social contact with his friends at the local parish. His older brother, with whom he was close, died recently. Until now, he says his “pride” has made him resist his primary care physician’s recommendation that he see a psychiatrist.
Late-life depressive syndromes commonly present with somatic complaints. Typically, patients deny having a mental illness and perceive that their symptoms are organic in origin (Box).1
Losses. Psychosocial and medical losses are major risk factors for late-life adjustment disorders, subsyndromal depressive disorders, and major depression. Medical losses may include loss of mobility or independent function, chronic pain, or sensory losses that limit one’s ability to read or hear. Psychosocial losses may include the death of a spouse, sibling, or peer or moving from one’s longtime home to a more structured environment (assisted living, nursing home, or living with relatives).
Medical causes to rule out before starting antidepressant therapy include:
- hypothyroidism
- medication side effects
- bipolar disorder, which may require the use of a mood-stabilizing agent to prevent manic symptoms.3
History. Often a history of mood disorder in the individual or a family member can help the clinician determine that mental illness accounts for the patient’s symptoms. In older patients, it is not uncommon for psychotic symptoms to accompany a primary mood disturbance.
Suicide risk is high in depressed older persons, so detection and quick treatment of depression is paramount. Older white men are at particularly high risk for completed suicide using firearms.3
Alcohol abuse may contribute to depressive symptoms in older persons. A second peak of alcoholism occurs in the eighth decade of life and can confound diagnosis of depression in patients of this age.
Making the diagnosis. In patients who present with symptoms and risk factors for late-life depression, depression rating scales can help confirm the diagnosis. Commonly used scales include the Beck Depression Inventory, the Hamilton Depression Rating Scale, and the Zung Self-Rating Depression Scale. Specialized scales for use in older patients include the Geriatric Depression Scale and the Cornell Scale; the latter scale is designed for patients with comorbid depression and dementia.3,4
Treatment
Antidepressant treatment in combination with psychotherapy usually is warranted when treating nonpsychotic late-life depression. In patients with psychosis, electroconvulsive therapy can help achieve remission.
Cognitive-behavioral therapy and interpersonal and insight-oriented psychotherapy have been shown to be effective in late-life depression. Social interventions aimed at preventing isolation also can work. In milder cases of depression, psychotherapy alone may be sufficient.3
Starting dosages. When antidepressant therapy is indicated in an older patient, start low and go slow.5 Older patients generally require prolonged titration rates and a longer course of treatment than do younger patients. Physiologic changes that occur with aging include:
- altered drug metabolism rate, including slower demethylation
- increased body fat-to-water ratio, which increases the volume of distribution for lipophilic psychotropic drugs
- decreased glomerular filtration rate, which may account for higher serum concentrations of drugs and their metabolites
- increased sensitivity of the older brain to the effects of medications.6
Thus—with some exceptions—recommended starting dosages for older patients are usually one-half those used in younger adults. For the frail older patient, the starting dosage should probably be even lower—about one-fourth the typical starting dosage in young adults.6 As in younger patients, the treatment goal is to achieve the maximal therapeutic effect with the lowest effective dosage while avoiding side effects.
More time may be required to achieve a therapeutic effect in older than in younger patients. Substantial improvement may not be seen until an older patient has been taking an antidepressant for 9 weeks or longer. In younger patients, responses are seen as early as 2 weeks after starting antidepressant therapy, and remission occurs within 6 to 8 weeks.2
SSRIs versus tricyclics
SSRIs—citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline (Table 1)7 —are considered first-line antidepressants for late-life depression. Although SSRIs and tricyclic antidepressants (TCAs) demonstrate equivalent efficacy in older adults, SSRIs are associated with lesstroublesome side effects.2
SSRIs are less sedating than tricyclics and are not associated with adverse effects on cognition; both qualities make these agents appropriate for older patients. Risk of overdose with SSRIs also is much lower than with TCAs.2
Both types of agent have been reported to cause movement disorders such as extrapyramidal symptoms and even tardive dyskinesia, but these side effects are much more rare with SSRIs than with TCAs.2 Also—unlike the TCAs— SSRIs do not significantly effect cardiac conduction, which is an important quality in the older population with its relatively high incidence of heart disease.
Table 1
USING SSRIs TO TREAT LATE-LIFE DEPRESSION
| Drug | Half-life (hours)* | Recommended dosage after age 65 (mg/d) † |
|---|---|---|
| Citalopram | 35 | 20 to 40 |
| Escitalopram | 27 - 32 | 10 to 20 |
| Fluoxetine | 96 - 386 | 10 to 60 |
| Fluvoxamine | 16 | 25 to 300 |
| Paroxetine | 21 | 10 to 40 |
| Sertraline | 26 | 25 to 200 |
| * In the older patient, medication half-lives may be extended 1.5to 2-fold. | ||
| † The heterogeneity of aging can lead to a wide variation in antidepressant target dosages. Therefore, although starting dosages for older adults are lower, final dosages may be the same as for younger adults. | ||
| Source: Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics Co, 2002. | ||
Meta-analyses suggest that patients are more likely to discontinue taking tricyclics than SSRIs.8 Adherence to antidepressant medications by older patients has been associated with lower perceived stigma of mental illness, higher self-rated severity of illness, age over 60, and absence of a personality disorder.9
SSRI side effects
The most common side effect of SSRIs is nausea, which is usually mild and occurs in the first weeks of treatment.2 Dry mouth is related to noradrenergic influences on the salivary gland. Anxiety is usually transient.
Sedation can be a problem in older patients who use SSRIs. Among the six SSRIs indicated for depression, paroxetine appears to be the most sedating.10 Paroxetine exhibits the most muscarinic blockade in vitro, with a binding affinity less than that of imipramine but greater than nortriptyline.11 Studies in older patients have suggested, however, that cognitive function is not compromised with paroxetine, as is observed with other antidepressants with anticholinergic action.6
Table 2
CYTOCHROME P450 ISOZYMES INHIBITED BY SSRI ANTIDEPRESSANTS (IN VITRO)
| Drug | 1A2 | 2C9 | 2C19 | 2D6 | 3A4 |
|---|---|---|---|---|---|
| Fluoxetine | + | ++ | + | +++ | ++ |
| Sertraline | + | + | + | + | + |
| Paroxetine | + | + | + | +++ | + |
| Citalopram | + | ○ | ○ | + | ○ |
| Escitalopram | ○ | ○ | ○ | ○ | ○ |
| Fluvoxamine | +++ | ++ | +++ | + | ++ |
| Source: Adapted from Greenblatt et al. J Clin Psychiatry 1998;59(suppl 15):19-27, and von Moltke et al. Drug Metab Dispos 2001;29:1102-9. | |||||
Sexual function can be diminished by SSRIs; the most common sexual side effects are anorgasmia and delayed orgasm.12 Preserving sexual function is important to many older men and women who retain their interest in sexual activity well into later life.
Withdrawal syndrome. Abrupt discontinuation of some SSRIs can lead to withdrawal side effects, such as dizziness, fatigue, and nausea. In a study of young and older adults, withdrawal syndrome followed abrupt discontinuation at rates of 14% with fluoxetine and 60% with sertraline or paroxetine.13
Elimination half-life. Medication half-lives tend to be prolonged in older patients because of age-related pharmacokinetic changes. SSRIs with relatively shorter half-lives—such as citalopram, sertraline, paroxetine, and fluvoxamine—could be eliminated fairly rapidly should adverse events arise.
On the other hand, use of a longer-acting agent, such as fluoxetine, may be an advantage if compliance is a problem. In this case, fluoxetine’s prolonged washout rate could help protect a patient from relapse, even when doses are missed.
Potential drug-drug interactions
Individual SSRIs have different effects on the cytochrome P450 system (Table 2).14,15 For example, fluoxetine, sertraline, and paroxetine—but not fluvoxamine—are in vitro inhibitors of the 2D6 isoenzyme system,16 which metabolizes TCAs, type Ic antiarrhythmics, alpha-adrenergic blockers, dextromethorphan, chemotherapeutic agents, and some antipsychotics. Citalopram has minimal inhibitory activity and escitalopram has virtually no inhibitory action on CYP 2D6.17
Cytochrome P450 3A4 metabolizes numerous drugs, including alprazolam, triazolam, carbamazepine, calcium channel blockers, and others. The 3A4 enzymes are inhibited by fluoxetine, sertraline, and fluvoxamine.18
Cytochrome P450 1A2 is the liver isoenzyme responsible for dealkylating theophylline, caffeine, and phenacetin. This enzyme system also metabolizes tacrine and clozapine. Of the SSRIs, fluvoxamine is the most potent inhibitor of the 1A2 enzyme, while escitalopram is a negligible inhibitor.17
Cytochrome P450 2C is a subfamily of isoenzymes that includes 2C9, 2C10, 2C19, and others. This system metabolizes some antidepressants as well as warfarin, phenytoin, and diazepam. Inhibitors of this system include fluvoxamine, fluoxetine, sertraline, and paroxetine.18
MAO inhibitors. Concomitant use of serotonin-acting drugs and monoamine oxidase inhibitors should be avoided. When used in combination, SSRIs and MAO inhibitors can cause a serotonin syndrome, with potential hyperpyretic crises, seizures, coma, and death. When switching medications, it is important to eliminate any serotonin-acting drug before starting an MAO inhibitor.2
In young adults, a 7-day washout is needed when switching from fluvoxamine and 14 days when switching from sertraline, citalopram, or paroxetine. With fluoxetine, the washout period is 35 days in young adults. Because medication half-lives in older patients may be prolonged two- to three-fold, it is advisable to proceed conservatively and extend these washout periods accordingly.
Related resources
- National Institute of Mental Health. Older adults: Depression and suicide facts. www.nimh.nih.gov/publicat/elderlydepsuicide.cfm
- WebMD Health/depression. http://my.webmd.com/condition_center/dep
- Salzman C, Wong E, Wright BC. Drug and ECT treatment of depression in the elderly, 1996-2001: a literature review. Biol Psychiatry 2002;52(3):265-84.
Drug brand names
- Alprazolam • Xanax
- Citalopram • Celexa
- Clozapine • Clozaril
- Diazepam • Valium
- Escitalopram • Lexapro
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Paroxetine • Paxil
- Sertraline • Zoloft
- Tacrine • Cognex
- Triazolam • Halcion
Disclosure
Dr. Kasckow reports that he receives grant/research support from, serves as a consultant to, or is on the speakers bureau of Eli Lilly and Co., Forest Laboratories, Pharmacia Corp., Solvay Pharmaceuticals, AstraZeneca Pharmaceuticals, Organon, Janssen Pharmaceutica, and Pfizer Inc.
Dr. Mohamed reports that she receives grant/research support from Forest Laboratories and serves on the speakers bureau of Eli Lilly and Co.
Dr. Herman reports that he serves as a consultant to Eli Lilly and Co.
Other co-authors report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
1. Judd LL, Paulus MP, Wells KB, Rapaport MH. Socioeconomic burden of subsyndromal depressive symptoms and major depression in a sample of the general population. Am J Psychiatry 1996;153:1411-7.
2. Mulchahey JJ, Malik MS, Sabai M, Kasckow JW. Serotonin selective reuptake inhibitors in the treatment of geriatric depression and related disorders. Int J Neuropsychopharmacol 1999;2:121-7.
3. Blazer DG, Koenig HG. Mood disorders. In: Busse EW, Blazer DG (eds). Textbook of geriatric psychiatry (2nd ed). Washington, DC: American Psychiatric Press, 1996;235-63.
4. Blazer DG. The psychiatric interview of the geriatric patient. In: Busse EW, Blazer DG (eds). Textbook of geriatric psychiatry (2nd ed). Washington, DC: American Psychiatric Press, 1996;175-89.
5. Young RC, Meyers BS. Psychopharmacology. In: Sadovoy J, Lazarus LW, Jarvik LF, Grossberg GP (eds). Comprehensive review of geriatric psychiatry, vol. II. Washington, DC: American Psychiatric Publishing, 1996;755:817.-
6. Dunner DL. Therapeutic considerations in treating depression in the elderly. J Clin Psychiatry 1994;55(suppl):48-58.
7. Physicians’ desk reference (56th ed). Montvale, NJ: Medical Economics Co, 2002.
8. Montgomery SA, Henry J, McDonald G, et al. Selective serotonin reuptake inhibitors: meta-analysis of discontinuation rates. Int Clin Psychopharmacol 1994;9:47-53.
9. Sirey JA, Bruce ML, Alexopoulos GS, Perlick DA, Friedman SJ, Meyers BS. Stigma as a barrier to recovery. Perceived stigma and patient-rated severity of illness as predictors of antidepressant drug adherence. Psychiatry Serv 2001;52:1615-20.
10. Dechant KL, Clissold SP. Paroxetine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in depressive illness Drugs 1991;41:225-53.
11. Richelson E. Pharmacology of antidepressants: characteristics of the ideal drug. Mayo Clin Proc 1994;69:1069-81.
12. Herman JB, Brotman AW, Pollack MH, Falk WE, Biederman J, Rosenbaum JF. Fluoxetine-induced sexual dysfunction. J Clin Psychiatry 1990;51:25-7.
13. Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998;44:77-87.
14. Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI. Drug interactions with newer antidepressants: role of human cytochromes P450. J Clin Psychiatry 1998;59(suppl 15):19-27.
15. von Moltke LL, Greenblatt DJ, Giancarlo GM, Granda BW, Harmatz JS, Shader RI. Escitalopram (s-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to r-citalopram. Drug Metab Dispos 2001;29:1102-9.
16. Nemeroff CB, DeVane CL, Pollock BG. Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996;153:311-20.
17. Owens MJ, Rosenbaum JF. Escitalopram: a second-generation SSRI. CNS Spectrums 2002;7(suppl 1):4.-
18. Preskorn SH. Recent pharmacologic advances in antidepressant therapy for the elderly. Am J Med 1993;94(suppl 5A):2S-12S.
1. Judd LL, Paulus MP, Wells KB, Rapaport MH. Socioeconomic burden of subsyndromal depressive symptoms and major depression in a sample of the general population. Am J Psychiatry 1996;153:1411-7.
2. Mulchahey JJ, Malik MS, Sabai M, Kasckow JW. Serotonin selective reuptake inhibitors in the treatment of geriatric depression and related disorders. Int J Neuropsychopharmacol 1999;2:121-7.
3. Blazer DG, Koenig HG. Mood disorders. In: Busse EW, Blazer DG (eds). Textbook of geriatric psychiatry (2nd ed). Washington, DC: American Psychiatric Press, 1996;235-63.
4. Blazer DG. The psychiatric interview of the geriatric patient. In: Busse EW, Blazer DG (eds). Textbook of geriatric psychiatry (2nd ed). Washington, DC: American Psychiatric Press, 1996;175-89.
5. Young RC, Meyers BS. Psychopharmacology. In: Sadovoy J, Lazarus LW, Jarvik LF, Grossberg GP (eds). Comprehensive review of geriatric psychiatry, vol. II. Washington, DC: American Psychiatric Publishing, 1996;755:817.-
6. Dunner DL. Therapeutic considerations in treating depression in the elderly. J Clin Psychiatry 1994;55(suppl):48-58.
7. Physicians’ desk reference (56th ed). Montvale, NJ: Medical Economics Co, 2002.
8. Montgomery SA, Henry J, McDonald G, et al. Selective serotonin reuptake inhibitors: meta-analysis of discontinuation rates. Int Clin Psychopharmacol 1994;9:47-53.
9. Sirey JA, Bruce ML, Alexopoulos GS, Perlick DA, Friedman SJ, Meyers BS. Stigma as a barrier to recovery. Perceived stigma and patient-rated severity of illness as predictors of antidepressant drug adherence. Psychiatry Serv 2001;52:1615-20.
10. Dechant KL, Clissold SP. Paroxetine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in depressive illness Drugs 1991;41:225-53.
11. Richelson E. Pharmacology of antidepressants: characteristics of the ideal drug. Mayo Clin Proc 1994;69:1069-81.
12. Herman JB, Brotman AW, Pollack MH, Falk WE, Biederman J, Rosenbaum JF. Fluoxetine-induced sexual dysfunction. J Clin Psychiatry 1990;51:25-7.
13. Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998;44:77-87.
14. Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI. Drug interactions with newer antidepressants: role of human cytochromes P450. J Clin Psychiatry 1998;59(suppl 15):19-27.
15. von Moltke LL, Greenblatt DJ, Giancarlo GM, Granda BW, Harmatz JS, Shader RI. Escitalopram (s-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to r-citalopram. Drug Metab Dispos 2001;29:1102-9.
16. Nemeroff CB, DeVane CL, Pollock BG. Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996;153:311-20.
17. Owens MJ, Rosenbaum JF. Escitalopram: a second-generation SSRI. CNS Spectrums 2002;7(suppl 1):4.-
18. Preskorn SH. Recent pharmacologic advances in antidepressant therapy for the elderly. Am J Med 1993;94(suppl 5A):2S-12S.