Using antipsychotics in patients with dementia
Careful dosing of atypicals plus psychosocial interventions can safely manage agitation and psychotic behavior
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.
