Overview. Behavioral problems are prevalent in later stages of Alzheimer’s disease, when 50-60% of patients develop severe psychotic symptoms (). Behavioral symptoms range from depression and apathy to delusions, hallucinations, and aggressiveness. They are extremely distressing and burdensome to caregivers and affect both the quality of patient care and the choice of treatment. Aggressive and psychotic symptoms in Alzheimer’s disease are preferentially treated with atypical antipsychotics, which are used off-label for Alzheimer’s disease.
Atypical antipsychotics are the therapy of choice among specialists because these agents generally do not cause the potentially serious extrapyramidal symptoms found with typical antipsychotics (such as haloperidol [McNeil’s Haldol, Dianippon’s Serenance, generics]). Extrapyramidal symptoms manifest as neuromuscular side effects that include dystonia (muscle spasms) and akathisia (muscle quivering and a sensation of restlessness).
In 2003, risperidone (Janssen’s Risperdal) and olanzapine (Eli Lilly’s Zyprexa) were the most commonly used atypical antipsychotics for the treatment of behavioral problems in Alzheimer’s disease. However, in February 2004, Lilly revised its U.S. label to include warnings that olanzapine is associated with an increased incidence of cerebrovascular adverse events and mortality when used in elderly patients with dementia. Risperidone’s labeling was also modified to include warnings regarding an increased incidence of cerebrovascular adverse events. In March 2004, the Committee for the Safety of Medicines (CSM) in the United Kingdom issued new guidelines recommending that neither risperidone nor olanzapine should be used to treat behavioral problems in elderly patients with dementia.
As a result, physicians have been more careful in choosing an antipsychotic to prescribe for Alzheimer’s disease. Many physicians have begun limiting their prescriptions for olanzapine and risperidone and opting for other antipsychotics, notably quetiapine (AstraZeneca’s Seroquel), instead. Preliminary data suggest that quetiapine is not associated with cerebrovascular events in elderly patients with dementia (). A recent small study found that quetiapine use in Alzheimer’s disease patients is associated with increased cognitive decline, a finding that could affect its sales in this market (). In addition, some physicians have begun using the newly launched atypical antipsychotic aripiprazole (Bristol-Myers Squibb’s Abilify) for patients with Alzheimer’s disease. This agent appears to have efficacy similar to that of olanzapine and risperidone in the treatment of schizophrenia but is associated with fewer side effects. Preliminary data suggest that aripiprazole is effective and well tolerated in patients with Alzheimer’s disease ().
Mechanism of Action. All atypical antipsychotics share a general mechanism of dual antagonism at serotonin and dopamine receptors. These drugs offer relief from symptoms of delusions, hallucinations, disorganized speech, and grossly disorganized or catatonic behavior by virtue of their dual antagonism of dopamine (D2) and serotonin (5-HT2a) receptors, which blocks the release of dopamine in the mesolimbic system. “Positive” psychotic symptoms such as hallucinations and delusions are alleviated by D2 receptor blockage whereas “negative” symptoms such as apathy may respond to serotonin receptor antagonism. In contrast, typical antipsychotics antagonize mainly the D2 receptors. Atypical antipsychotics differ from typical antipsychotics with respect to their biochemical profiles and tolerability by patients: atypical antipsychotics are better tolerated and generate fewer extrapyramidal symptoms than typical antipsychotics. These variations, along with their receptor-binding profiles, may reflect different modes of action and result in different clinical profiles for atypical and typical antipsychotics.
Because acetylcholinesterase inhibitors appear to alleviate symptoms of apathy and visual hallucinations in Alzheimer’s disease (with less effect on other Alzheimer’s disease behavioral symptoms, such as repetitive behaviors), it has been suggested that the death of cholinergic neurons in the basal forebrain interrupts their transmission to postsynaptic monoaminergic neurons in the limbic, paralimbic, and cortical regions. Antipsychotics probably compensate for the loss of cholinergic neuron signaling to monoaminergic neurons by directly affecting the dopaminergic and serotonergic brain centers.
Formulation. An oral formulation is used for long-term treatment of behavioral problems in Alzheimer’s disease, an intramuscular injection formulation is occasionally used in acute dementia-related agitation, and a depot formulation is employed in rare cases of noncompliant long-term use for Alzheimer’s disease.
Risperidone (Janssen’s Risperdal) () is widely used off-label in low doses (0.5-2.0 mg) in its oral form to manage psychotic symptoms in Alzheimer’s disease. Risperidone and olanzapine were the most commonly used antipsychotics in 2003 in the major markets and are largely similar in terms of their efficacy in the treatment of Alzheimer’s disease. Historically, risperidone was the first choice for two main reasons: (1) it was the first atypical antipsychotic to demonstrate efficacy in relieving behavioral and psychological symptoms of dementia, and (2) it has less anticholinergic activity than olanzapine and is therefore more safely administered to Alzheimer’s disease patients who are receiving AChEI therapy. However, the risk of cere-brovascular adverse events associated with risperidone treatment in the elderly is expected to decrease the use of risperidone in the Alzheimer’s disease population and increase the use of other atypical antipsychotics, such as quetiapine and aripiprazole.
In addition to its original oral tablet form, risperidone is available in an oral solution (Risperdal Oral Solution), rapidly disintegrating oral tablets (Risperdal M-Tab), and a long-acting depot formulation (Risperdal Consta) that is administered every two weeks. These three formulations are intended to improve compliance.
Janssen is attempting to obtain an approval of risperidone specifically for psychosis associated with Alzheimer’s disease. In 1998, three European countries (Austria, Finland, and Portugal) approved risperidone for use in the treatment of psychotic symptoms associated with dementia. Further approvals for this new indication were expected to follow in the rest of Europe, but the company did not file for this indication in Italy until 2002. Janssen filed for approval of risperidone in the treatment of psychosis in Alzheimer’s disease in the rest of the EU in January 2003. Also, in 1998, Janssen submitted an NDA to the FDA for risperidone for the short-term symptomatic management of inappropriate behavior due to aggression and/or psychosis associated with severe dementia. This filing was significantly delayed by the FDA’s decision to review how it evaluates drugs to treat behavioral symptoms of Alzheimer’s disease. After finishing this review in 2000, the FDA informed Janssen that an additional Phase III study was required for the drug to secure approval for the treatment of behavioral symptoms relating to Alzheimer’s disease. These trials are currently under way in the United States. Phase III trials are ongoing in Japan.
Risperidone is the most potent of the currently marketed D2 and 5-HT2A receptor antagonists. It has a higher affinity for 5-HT2A than for D2 receptors and therefore has a lower rate of extrapyramidal symptoms than agents with higher affinity for the D2 receptor, such as haloperidol. In addition, it appears to offer relief from symptoms of delusions, hallucinations, disorganized speech, and grossly disorganized or catatonic behavior by virtue of its dual antagonism of dopamine (D2) and serotonin (5-HT2a) receptors, which blocks the release of dopamine in the mesolimbic system. Finally, risperidone has only weak anti-cholinergic properties.
A double-blind study demonstrated a therapeutic effect of risperidone on the aggression, agitation, and psychosis of patients with dementia (). The study randomly assigned 345 patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of dementia (including Alzheimer’s disease, vascular dementia, or mixed dementia), a minimum aggression score of >4 on the Functional Assessment Staging Test (FAST), and an MMSE score of <23 to groups treated with up to a maximum of 2 mg/day of risperidone or placebo for 12 weeks. Behavior was assessed using the Cohen-Mansfield Agitation Inventory (CMAI), the Behavioral Pathology in Alzheimer Disease (BEHAVE-Alzheimer’s disease) scale, the Clinical Global Impressions of Severity scale (CGIS), and the CGIC. Upon completion, patients receiving risperidone improved significantly over those receiving placebo on CMAI and BEHAVE-Alzheimer’s disease scores (p < 0.001). In addition, patients treated with risperidone showed improvement on verbal, physical, and psychosis scales as compared with patients receiving placebo at 12 weeks. Treated patients also showed symptoms of “mild” severity on the BEHAVE-Alzheimer’s disease scale versus “moderate” levels of severity for patients in the placebo group.
The D2 receptor affinity of this atypical antipsychotic causes dose-dependent extrapyramidal symptoms, especially at doses above 6mg daily. While Alzheimer’s disease patients are treated with lower doses of risperidone (0.5 mg to 2.0 mg) and therefore are less at a risk for extrapyramidal symptoms, their frailty due to their age still renders these symptoms a major cause of concern. Other side effects linked to risperidone include orthostatic hypotension, weight gain, and sedation. Because of the risk of orthostatic hypotension during the initial treatment period, risperidone is usually titrated over a three-day period.
In March 2004, the CSM advised U.K. physicians against using this agent in their elderly patients with dementia. In April 2003, warnings regarding an increased risk of cerebrovascular adverse events (including stroke) in elderly patients with dementia were added to risperidone’s U.S. label. These actions were based on data from four placebo-controlled trials that enrolled a total of approximately 1, 200 elderly patients with dementia (Risperdal Letter to Healthcare Professionals, April 16, 2003). Pooled analysis of these trials, which ran from one to three months, found the incidence of all cerebrovascular events to be statistically greater with risperidone than with placebo (3.8% versus 1.5%, respectively). Of note, there was no statistical difference between risperidone and placebo in the incidence of serious cerebrovascular events (1.6% versus 0.6%, respectively; p = 0.469). The mortality rate due to cerebrovascular events was similar for risperidone (0.5%) and placebo (0.2%). In two of the trials, there was a higher occurrence of cerebrovascular events in patients taking risperidone than in those taking placebo; in the other two trials, the rates were similar between groups. Other European nations are evaluating the risks associated with risperidone and, if necessary, advice will be issued.
Some U.K. physicians feel that the CSM’s recommendations to avoid the use of risperidone for the treatment of psychosis in dementia may prove detrimental to patients (). Specifically, they argue that treatment with antipsychotics should be a balanced decision weighing the benefits of reducing agitation and aggression, which can be debilitating to patients and caregivers alike, with the potential risk of stroke, which they argue is a quantifiable rare “excess risk.” Furthermore, they worry that the blanket injunction issued by the CSM (instead of suggestive guidance on risk-benefit prescribing) on risperidone and olanzapine will encourage physicians (especially GPs) to use typical antipsychotics, which are associated with more anticholinergic and parkinsonian side effects than their atypical counterparts. Furthermore, a recent study demonstrated no significant difference in the risk of stroke between typical and atypical antipsychotics ().