The psychiatrist started galantamine, 4 mg bid, and vitamin E, 400 IU bid, to maximize her cognition and attempt to slow her functional decline. Ms. A, who was in an assisted living facility when we evaluated her, was transferred to the facility’s nursing section shortly afterward.
At follow-up 3 weeks later, Ms. A’s behavior improved moderately, but she remained unpredictable and intermittently agitated. Staff reported that she was physically assaulting caregivers two to three times weekly.
Which medication(s) would you use to control Ms. A’s agitation and paranoia?
- an SSRI
- a mood stabilizer
- an atypical antipsychotic
- a combination or two or more of these drug classes
The authors’ observations
Aside from controlling agitation, medication treatment in AD should slow cognitive decline, improve behavior, help the patient perform daily activities, and delay nursing home placement.
- Watch for drug-drug interactions. Many patients with AD also are taking medications for hypertension, hypercholesterolemia, diabetes, arthritis, and other medical comorbidities.
- Start low and go slow. Older patients generally do not tolerate rapid dos-ing adjustments as well as younger patients (Table 2).
SSRIS. Selective serotonin reuptake inhibitors increase serotonin at the synaptic terminal. Serotonin has long been associated with impulsivity and aggression, and decreased 5-hydroxyindole acetic acid, a metabolite of serotonin, has been found in violent criminals and in psychiatric patients who have demonstrated inward or outward aggression.11
SSRIs generally are tolerable, safe, effective, and have little cholinergic blockade. Citalopram and sertraline minimally inhibit the cytochrome P-450 2D6 isoenzyme and have lower proteinbinding affinities than fluoxetine or paroxetine. Thus, citalopram and sertraline are less likely to alter therapeutic levels of highly bound medications through displacement of either drug’s protein-bound portion.10
Anticonvulsants with mood-stabilizing effects are another option. Reasonably strong data support use of divalproex for managing agitation in AD, either as a first-line agent or as an adjunct after failed SSRI therapy. Unlike other anticonvulsants, divalproex also may be neuroprotective.3
Divalproex, however, is associated with white blood cell suppression, significant liver toxicity, and pancreatitis, although these effects are rare.13 Monitor white blood cell counts and liver enzymes early in treatment, even if divalproex blood levels below the standard reference range produce a response.14
Though not studied specifically for treating agitation in AD, carbamazepine has demonstrated significant short-term efficacy in treating dementia-related agitation and aggression.2 Scant data support use of gabapentin or lamotrigine in Alzheimer’s dementia, but these agents are often used to manage agitation in other disorders.
Atypical antipsychotics. Psychosis usually occurs in middle-to-late-stage AD but can occur at any point. If psychosis occurs early, rule out Lewy body dementia.15
Choose an atypical antipsychotic that exhibits rapid dopamine receptor dissociation constants to reduce the risk of extrapyramidal symptoms, tardive dyskinesia, and cognitive decline with prolonged use. Quetiapine has shown efficacy for treating behavioral problems in Alzheimer’s and Lewy body dementia,7 and its sedating effects may help regulate sleep-wake cycles.
Data support use of olanzapine for agitation in AD,6 but watch for anticholinergic effects including worsening of cognition. Fast-dissolving olanzapine and risperidone oral wafers may help circumvent dosing difficulties in patients who cannot swallow—or will not take—their medication. Intramuscular olanzapine and ziprasidone have shown efficacy in treating acute agitation, but no systematic studies have examined their use in agitation secondary to dementia.
Recent data suggest a modestly increased risk of cerebrovascular accidents in AD patients taking atypicals compared with placebo, but the absolute rate of such events remains low.
Treatment: 3 months of stability
Ms. A’s galantamine dosage was increased to 8 mg bid and sertraline—25 mg/d for 7 days, then 50 mg/d—was added in an effort to better control her agitation, but the behavior continued unabated for 2 weeks. Divalproex, 125 mg bid titrated over 4 weeks to 750 mg/d, was added. Still, her agitation persisted.
Over the next 4 to 6 weeks, Ms. A showed signs of psychosis, often talking to herself and occasionally reporting “people attacking me.” She became paranoid toward members of her church, who she said were “trying to hurt” her. The paranoia intensified her agitation and disrupted her sleep. Physical examination was unremarkable, as were chest X-ray and urinalysis.
Sertraline and divalproex were gradually discontinued. Quetiapine—25 mg nightly, titrated across 2 weeks to 150 mg nightly—was started. Ms. A’s agitation and psychosis decreased with quetiapine titration, and her sleep improved. Her paranoid delusions remained but no longer impeded functioning or prompted a violent reaction.
Then after remaining stable for about 3 months, Ms. A’s paranoid delusions worsened and her agitation increased.
What treatment options are available at this point?
The authors’ observations