Medication Summary
As yet, no compelling data indicate that medications can decrease the rate of cognitive decline. Medications can be used to treat agitation and hallucinations, as well as depression, and to improve cognition and/or alertness.
Acetylcholinesterase inhibitors should usually be the first drugs used to treat hallucinations and agitation in patients with dementia with Lewy bodies (DLB). Studies also indicate that administering cholinesterase inhibitors to these patients can improve neuropsychological test scores. [23]
Regarding nonspecific partial glutamate antagonists, memantine has been approved in the United States for the treatment of moderate to severe Alzheimer disease. It is not approved for the treatment of Parkinson disease or DLB.
A double-blind, placebo-controlled, multicenter trial of memantine in 72 patients with DLB or Parkinson disease dementia found that after 24 weeks of treatment, patients taking memantine had better clinical global impression of change scores than did those taking placebo. [24, 25] A few case reports have noted that memantine may exacerbate fluctuations.
Although clonazepam has been considered the treatment of choice for rapid eye movement sleep behavior disorder in patients with DLB, melatonin may be beneficial, either alone or in combination with clonazepam. Melatonin may be administered at 3mg at bedtime. [27]
Cholinesterase Inhibitors
Class Summary
ACh concentrations are decreased in the brains of patients with DLB. Patients with DLB are more likely than patients with Alzheimer disease to improve with cholinesterase inhibitor therapy. Fluctuations in cognition may decrease, alertness may increase, and memory may improve.
Donepezil (Aricept)
Donepezil noncompetitively inhibits centrally active acetylcholinesterase, which may increase concentrations of ACh available for synaptic transmission in the central nervous system (CNS).
Rivastigmine (Exelon)
This agent is a competitive and reversible inhibitor of acetylcholinesterase. Although the drug's mechanism of action is unknown, it may reversibly inhibit cholinesterase, which may, in turn, increase concentrations of ACh available for synaptic transmission in the CNS and enhance cholinergic function. Rivastigmine's effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. No evidence indicates that acetylcholinesterase inhibitors alter the course of underlying dementia.
Galantamine (Razadyne, previously called Reminyl)
Galantamine is a competitive and reversible inhibitor of acetylcholinesterase. Although its mechanism of action unknown, the drug may reversibly inhibit cholinesterase, which may, in turn, increase concentrations of ACh available for synaptic transmission in the CNS and enhance cholinergic function. Galantamine's effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. No evidence indicates that acetylcholinesterase inhibitors alter the course of underlying dementia. Galantamine is available in extended-release (ER) daily dosing and in immediate-release (IR) form.
Rivastigmine (Exelon patch)
Rivastigmine is a competitive and reversible acetylcholinesterase inhibitor. Although its mechanism of action is unknown, it may reversibly inhibit cholinesterase, which may, in turn, increase concentrations of ACh available for synaptic transmission in the CNS and thereby enhance cholinergic function. Rivastigmine's effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact.
Rivastigmine is available as a 5cm2 patch containing 9 mg (releases 4.6 mg/24 h) and a 10-cm2 patch containing 18 mg (releases 9.5 mg/24 h). The drug is indicated for dementia of Alzheimer disease and for dementia associated with Parkinson disease.
Antipsychotics, 2nd Generation
Class Summary
Patients with DLB frequently have hallucinations that can cause them to engage in unsafe behavior; these patients therefore require treatment. Standard neuroleptics exacerbate parkinsonian motor features and, consequently, are contraindicated.
Clozapine (Clozaril, FazaClo)
Clozapine is associated with the risk of agranulocytosis when it is used at doses required for the treatment of schizophrenia with symptoms refractory to standard neuroleptics. In the United States, weekly dosing and a weekly CBC are required to dispense the drug. Discontinuing therapy at the first sign of leukopenia decreases, but does not eliminate, the risk of agranulocytosis. Whether agranulocytosis is associated with low doses in elderly patients and in patients with dementia is not clear.
Quetiapine (Seroquel)
Quetiapine is an atypical neuroleptic that may act by antagonizing dopamine and serotonin effects. It is also used to treat insomnia.
Aripiprazole (Abilify)
Aripiprazole improves positive and negative schizophrenic symptoms. Its mechanism of action unknown, but it has been hypothesized that the drug works differently than other antipsychotics do. Aripiprazole is thought to be a partial dopamine (D2) and serotonin (5HT1A) agonist and to antagonize serotonin (5HT2A). Additionally, no QTc interval prolongation has been noted in clinical trials. Aripiprazole is available as a tablet, an orally disintegrating tablet, and an oral solution.
Antidepressants
Class Summary
Depression is frequent in DLB. Antidepressants with little or no anticholinergic activity are desirable.
Venlafaxine (Effexor)
Venlafaxine may treat depression by inhibiting neuronal serotonin and norepinephrine reuptake. In addition, it causes beta-receptor down-regulation.
Paroxetine (Paxil, Pexeva)
Paroxetine selectively inhibits presynaptic serotonin reuptake, with minimal or no effect on the reuptake of norepinephrine or dopamine.
Sertraline (Zoloft)
Sertraline selectively inhibits presynaptic serotonin reuptake.
Fluoxetine (Prozac)
Fluoxetine selectively inhibits presynaptic serotonin reuptake, with minimal or no effect on the reuptake of norepinephrine or dopamine. The drug may cause more gastrointestinal adverse effects than do other currently available SSRIs, which is why it is not recommended as a first treatment choice. Fluoxetine may be given as a liquid and a capsule.
The drug may be administered in 1 dose or in divided doses. The presence of food does not appreciably alter levels of the medication. Fluoxetine may take up to 4-6 weeks to achieve steady-state levels, as it has the longest half-life (72 h).
Fluoxetine's long half-life is an advantage and a drawback. If the drug works well, an occasional missed dose is not a problem, but if problems occur, eliminating all active metabolites takes a long time. The choice depends on adverse effects and drug interactions. Adverse effects of SSRIs seem to be quite idiosyncratic; thus, relatively few reasons exist to prefer one over another at this point if dosing is started at a conservative level and advanced as tolerated.
Benzodiazepines
Class Summary
By binding to specific receptor sites, these agents appear to potentiate the effects of gamma-aminobutyric acid (GABA) and to facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.
Clonazepam (Klonopin)
Clonazepam is a long-acting benzodiazepine that increases presynaptic GABA inhibition and reduces monosynaptic and polysynaptic reflexes. It suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters. Clonazepam has multiple indications, including the suppression of myoclonic, akinetic, or petit mal seizure activity and focal or generalized dystonias (eg, tardive dystonia). The drug reaches peak plasma concentration at 2-4 hours after oral or rectal administration.
In patients who are dependent, clonazepam is used in a manner similar to phenobarbital to smoothly wean patients from short-acting benzodiazepines. The general principle is that sedatives with longer half-lives have less severe withdrawal symptoms. Various schemes are used to individualize the dose to the patient. If symptoms are severe enough to require inpatient treatment, intravenous lorazepam or diazepam is used.
Dopamine precursors
Class Summary
Patients with DLB have impaired dopaminergic tone due to disease in the substantia nigra and possibly other dopaminergic nuclei. The efficacy of the treatment of motor features in DLB depends on where the patient is on the Parkinson disease ̶ DLB spectrum. Whether or not levodopa influences cognition positively or negatively remains controversial, and its effect on cognition is probably modest.
Levodopa and carbidopa (Sinemet, Parcopa)
Levodopa is a large, neutral amino acid absorbed in the proximal small intestine by the saturable carrier-mediated transport system. Absorption is decreased by meals that include other large, neutral amino acids (although only patients with meaningful motor fluctuations need to consider a low-protein or protein-redistributed diet). The drug's half-life is approximately 2 hours.
Provide at least 70-100 mg/day of carbidopa; if more is required, substitute a 25/100 tablet for each 10/100 tablet. When more levodopa is required, substitute a 25/250 tablet for the 25/100 or 10/100 tablet. The controlled-release (CR) formulation is absorbed more slowly and provides more sustained levodopa levels than IR form does.
When it is initially required, the CR form is as effective as the IR form and may be more convenient. Patients with dissipating motor fluctuations and no dyskinesia often benefit from prolongation of the short-duration response when switched from the IR to the CR form. Patients with meaningful fluctuations and dyskinesia often have increased dyskinesia when switched to the CR form. Doses and intervals for the CR form may be increased or decreased to response.
Most patients are adequately treated with 2-8 tablets daily in doses divided every 4-8 hours when the patient is awake. Allow at least 3 days between dose adjustments. Levodopa/carbidopa may be administered as a whole or half tablet, which should not be crushed or chewed. Motor symptoms and signs may or may not improve.
