General guidelines for psychotropic medication use in frail elderly patients are applicable. Systematic evidence to support the effectiveness of particular psychotropic drugs in dementia patients is limited. Therefore, choice of drug class may be based on clinical evidence, and choice of agent is often based on the side-effect profile and on the characteristics of a given patient. Noncognitive, psycho-pathological, and behavioral manifestations in patients with dementia may be early targets for psychiatric intervention.
Treatment of Psychosis and Agitation
There is some evidence of the effectiveness of antipsychotics to control agitation, aggressiveness, wandering, and psychotic symptoms in patients with dementia. The data suggest that improvement is greater for psychosis than for other symptoms. Antipsychotics are often administered in the evening so that maximum levels occur at sleep time. Most antipsychotics have long half-lives, so once-a-day doses may be sufficient. Oral administration is preferred, except in cases of emergency or when the patient is unable to take the medication by mouth. Initial treatment with low doses of a high-potency agent, such as haloperidol (0.5-2.0 mg/day; maximum dosage = 5 mg/day), maybe recommended, and evidence indicates that it is effective in reducing aggressiveness in agitated dementia. However, the atypical antipsychotics cause fewer extrapyramidal effects, and their use in dementia has been supported by studies of risperidone (0.5-2.0 mg/ day; maximum dosage = 6 mg/day), olanzapine (5-10 mg/day), quetiapine (25-100 mg/day), and ziprasidone (20-40 mg/day). Another option is clozapine (maximum dose = 100 mg/day), which may be the best choice for Parkinson’s disease or dementia with Lewy bodies but carries risk of agranulocytosis. Thioridazine has been in wide clinical use in some countries for controlling behavior in patients with dementia. However, it has high anticholinergic activity and may cause worrisome QT prolongation. Furthermore, a systematic review suggested that no evidence supports its use in dementia.
There is less empirical support for, but considerable clinical experience with, the use of other medications in cases of agitated behavior, particularly in milder cases or cases unresponsive to neuroleptics. These medications include trazodone (50-400 mg/day; higher doses have been reported by some clinicians), buspirone (15-50 mg/day), carbamazepine (400-1,200 mg/day; maximum blood levels = 8-12 mg/mL) (), and gabapentin (400-1,200 mg/day). These medications may be particularly useful in cases of dementia with Lewy bodies because the likelihood of severe adverse side effects with the use of neuroleptics is quite high. Anticonvulsants require close monitoring because of potential toxic effects. Several other agents have been proposed for the treatment of agitation in patients with dementia, including benzodiazepines and beta-blockers, but evidence of efficacy is very limited, and potential side effects preclude routine recommendation.
Treatment of Depression
Both well-designed studies and reviews of randomized controlled trials suggest that antidepressants may be effective for treating depressive syndromes in patients with dementia. Improvement of both cognitive function and apathy, especially in frontal lobe dementias, is also a frequent target in the treatment of depression. However, because antidepressants do have side effects, clinicians should prescribe with due caution. The newer antidepressants, particularly the selective serotonin reuptake inhibitors (SSRIs), are widely considered to be first-line treatment and should be preferred because of their favorable side-effect profile. SSRIs used in dementia include fluoxetine (initial dosage = 5-10 mg/day, increase at several-week intervals to 40-60 mg/day); paroxetine (same dosages, increase every 1-2 weeks because of shorter half-life); sertraline (initial dosage = 25 mg/day, increase at 1- to 2-week intervals to 150-200 mg/day); and citalopram (initial dosage = 10 mg/day, increase at weekly intervals to a maximum dosage of 40 mg/day). Escitalopram (10-20 mg/day) is promising. Aside from well-known gastrointestinal symptoms, some potential SSRI side effects, such as agitation, akathisia and other extrapyramidal symptoms, dizziness, and weight loss, require monitoring in dementia patients. Venlafaxine (initial dosage = 18.75-37.50 mg twice a day, increase at weekly intervals to 350-375 mg/day) is also recommended, particularly in apathetic patients because of stimulating effects, but it may elevate blood pressure at higher doses. Trazodone (initial dosage=2 5-50 mg/day, increase at weekly intervals to 300-400 mg/day) is often recommended when sedation and improved sleep are desired. Trazodone’s main risks in elderly patients with dementia are orthostatic hypotension and excessive sedation.
Classic cyclic antidepressants usually are not considered first-line treatment because they have more adverse effects such as orthostatic hypotension, delays in cardiac conduction, anticholinergic effects, impaired cognition, and delirium. However, some clinicians prefer these drugs, particularly in treating severe depressive syndromes. In such cases, because of a more favorable side-effect profile, the recommended drugs are nortriptyline, particularly when sedation is needed (initial dosage = 10-25 mg/day, increase at weekly intervals to 100-150 mg/day; blood levels should not exceed 100-150 m /mL), and desipramine (initial dosage=2 5-50 mg/day, increase at weekly intervals to 200 mg/day; blood levels should not exceed 150-200 mg/mL). There is also considerable experience with nortriptyline in “organic” depression, and clinical experience and some reports support the use of SSRIs and nortriptyline in pathological crying. In depressed patients with frontotemporal dementia, both SSRIs and trazodone have shown some benefit.
Evidence is limited on the beneficial effects of other drugs recommended in the treatment of depression or depression-associated symptoms in dementia patients, such as bupropion, which may increase the risk of seizures at high doses, or buspirone for the treatment of agitation and anxiety associated with depression. Monoamine oxidase inhibitors (MAOIs) should be used only if other drugs fail, because postural hypotension is a serious problem in frail elderly, and patients with dementia cannot be trusted to avoid restricted foods. Psychostimulants, such as D-amphetamine and methylphenidate, are sometimes useful in patients with medical illness and depression; potential side effects of restlessness, agitation, sleep disturbances, and appetite suppression are uncommon at low doses. Apathy in depressed dementia patients also has been treated with bromocriptine, whereas potential side effects, such as psychosis, confusion, dyskinesias, and anticholinergic effects, including delirium, have been reported after treatment with amantadine. Clinical experience suggests that electroconvulsive therapy (ECT) may be useful in treating severe depression associated with dementia that does not respond to drugs, but the data are limited. In such cases, ECT should be given twice rather than thrice weekly, and less memory loss has been documented with unilateral than with bilateral placement of electrodes (American Psychiatric Association 1997).
Treatment of Insomnia and Anxiety
Sleep disturbances, which are frequent in patients with dementia, should be primarily managed by careful attention to sleep hygiene. When the disturbances occur in patients with other neuropsychiatric symptoms requiring psychotropic treatment, a drug with sedating properties, given at bedtime, probably should be selected. Otherwise, trazodone (50-100 mg, once at bedtime) is often prescribed. Clinical experience suggests that low-dose anti-psychotics (haloperidol 0.5-1.0 mg or the atypical antipsychotics) can be helpful. Chloral hydrate (250-500 mg/ day) and zolpidem (5-10 mg at bedtime) are good alternatives for short-term use. Clonazepam (0.5 mg/day, with increases in dosage up to 2 mg/day) is recommended by some clinicians in patients with frequent awakening or nocturnal wandering. However, all hypnotics have the potential risk of causing nocturnal confusion, daytime sedation, tolerance, rebound insomnia, worsening cognition, disinhibition, and delirium. Triazolam is not recommended because of its association with amnesia. Many patients use diphenhydramine because it is available in a variety of nonprescription preparations and therefore is erroneously believed to be safe. It is not a good choice because of its anticholinergic properties, which may exacerbate confusion and also counteract the effects of cholinesterase inhibitors.
The use of benzodiazepines for anxiety in patients with dementia is controversial because of the side-effect profile described, which also includes ataxia and accidental falls, respiratory depression, and agitation among the most disturbing effects in dementia patients. Low dosages of relatively short-acting drugs, such as lorazepam (0.5-1.0 mg every 4-6 hours) or oxazepam (7.5-15.0 mg four times per day), are preferred when using benzodiazepines and may be beneficial for brief periods. Antidepressants should be considered for long-term treatment, but empirical evidence is very limited regarding their use for anxiety in dementia patients.
Treatment of Cognitive Deficits
Pharmacological treatment of DAT also should aim at restoring cognitive function and associated functional losses. Currently, the main drugs approved act by inhibiting acetylcholinesterase and thus providing cholinergic augmentation. They may improve cognitive and behavioral symptoms, as well as functional ADLs, in patients with mild to moderate DAT. However, the degree of benefit achieved is limited or symptomatic () — that is, with little proven effect on the ultimate outcome. Tacrine, which was approved for treating DAT in 1993, has since been replaced by a group of drugs with fewer adverse affects, which include donepezil, rivastigmine, and galantamine.
To date, there are no head-to-head comparisons of cholinesterase inhibitors, and the main differences between these drugs are in safety profiles and ease of administration (one to two times daily administration). Donepezil is the most widely prescribed, probably because it was the first one to appear (Organization for Economic Cooperation and Development, in press). One cost-effectiveness analysis of cholinesterase inhibitors supported their use, but medical guidelines in many countries recommend that cholinergic augmentation therapy be used only in patients with mild to moderate forms of DAT (MMSE score > 10 or 12 points or the equivalent score on the Alzheimer’s Disease Assessment Scale — cognitive subscale [ADAS-Cog]). However, positive results have been documented in moderate to severe cases of DAT with a new drug, memantine. It blocks the effects of glutamate in stimulating the N-methyl-D-aspartate receptor. A Cochrane review concluded that the evidence to date shows that in moderate to severe DAT, memantine improves measures of cognition and functional decline but does not affect clinically discernible change or improve global measures of dementia. A randomized, placebo-controlled trial of memantine in patients with moderate to severe Alzheimer’s disease who were already receiving donepezil found statistically significant but clinically modest benefits.
Cholinesterase inhibitors show some promise in the treatment of other dementias, such as dementia with Lewy bodies and Parkinson’s disease. Furthermore, pharmacological studies supporting the use of these and other agents have heuristic value in stimulating research on the pathogenesis of neurodegenerative dementias.
An antioxidant, vitamin E (200-2,000 IU/day), is frequently recommended for DAT patients to prevent further decline (American Psychiatric Association 1997). Recommendations were based on both empirical evidence and clinical experience. Although a recent, systematic review found no evidence to support its use, vitamin E appears to be very safe and is still considered by some clinicians for treatment of DAT, particularly in the moderately severe stage, alone or in combination with an anticholinergic agent. Lower dosages should be used in patients with vitamin K deficiency because vitamin E may worsen coagulation deficits.
Positive results with a wide variety of agents to treat DAT have been reported, and systematic reviews support the benefits of nimodipine (90 mg/day), a calcium channel blocker; nicergoline, an ergot derivative (); and selegiline, a monoamine oxidase-B (MAO-B) inhibitor. Selegiline (5-10 mg/day) may delay cognitive deterioration and may be worth considering in patients who are intolerant of, or unresponsive to, cholinesterase inhibitors. It requires no dietary limitations as with other MAOIs, but a major side effect is orthostatic hypotension.
Beneficial effects have been claimed, but not proven, with several agents, including statin therapy for lowering serum cholesterol; dehydroepiandrosterone; estrogen replacement therapy in postmenopausal women; and ginkgo biloba, an extract of the leaves of the maidenhair tree. No evidence has been found for the use of hydergine, an ergo-loid mesylate, in DAT, but it may be appropriately continued for patients who have experienced benefits (American Psychiatric Association 1997). Preventive treatment with antihypertensive drugs is also controversial, but the results of a large international trial with candesartan in mild hypertension are promising. In view of recent findings related to vascular factors influencing the cognitive symptoms of DAT, the management of these factors has become a focus of attention, discussed later in this section in relation to vascular dementia.
Finally, systematic reviews do not support the use of indomethacin, a nonsteroidal anti-inflammatory drug; piracetam, a nootropic agent with effects on increasing oxygen and glucose utilization and probable platelet antiaggregation properties; lecithin, a major dietary source of choline; D-cycloserine, an antibiotic that enhances glutamate function; and nicotine. Future drugs may strategically aim to retard or prevent amyloid deposition and neuronal degeneration and to stimulate neuroprotection. The development of an experimental vaccine directed against the formation and accumulation of amyloid plaques has shown promise.
Drug treatment of mild cognitive impairment is controversial because evidence supporting pharmacological strategies remains limited. Efficacy of nicergoline and the dopamine receptor agonist piribedil has been reported, and results of a meta-analysis support the use of acetyl-L-carnitine. Several long-term clinical trials are still ongoing (antioxidants, nootropics, anticholinesterases). Prevention and disease-modifying strategies raise ethical questions because interventions are focused on nondiseased elderly at risk, which means that long-term safety should be given disproportionate emphasis compared with efficacy. At present, treatment strategies for DAT could be extrapolated to mild cognitive impairment. We recommend follow-up and monitoring of individuals with mild cognitive impairment, especially when neuroimaging suggests a high probability of conversion to DAT (see “Neuroimaging and Electroencephalography”). Early treatment should be considered as soon as the diagnosis of dementia is clear.
Vascular dementia has no standard treatment, but recently, symptomatic cholinergic treatment has shown promise in both Alzheimer’s disease with vascular dementia and vascular dementia alone. Systematic reviews give specific support to memantine, nicergoline, and nimodipine in both vascular dementia and mixed dementia. Evidence is limited on the primary prevention and secondary prevention of vascular dementia, but treating associated medical conditions and reducing known cardiovascular and cerebrovascular risk factors seem logical steps. Daily aspirin therapy to inhibit platelet aggregation has been recommended but remains controversial and is not supported by the results of a recent systematic review. The preventive effects of early treatment of even mild hypertension are also promising for vascular dementia, but no convincing evidence has been found so far relating diabetic treatment to the prevention or management of cognitive impairment in type 2 diabetes. More studies are needed of the effectiveness and efficacy of prevention and treatment of mild cognitive impairment of vascular origin. In the meantime, good clinical sense recommends symptomatic treatment and control of other treatable risk factors — namely, cardiac disease, hyperlipidemia, obesity, hyperhomocysteinemia, hyperfibrinogenemia, and other conditions that can cause brain hypoperfusion, such as obstructive sleep apnea and orthostatic hypotension. Psychiatrists can play a prominent role in treating and preventing smoking and alcohol dependence. Genetic counseling may be considered in diseases of genetic basis, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
Selections from the book: “Textbook of Psychosomatic Medicine”, 2005.