Review
Use of antipsychotics in elderly patients with dementia: Do atypical and conventional agents have a similar safety profile?

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Abstract

Pharmacological treatment of dementia addresses two main clinical features of the disease: cognitive deterioration with predominantly memory loss and behavioural and psychological symptoms (BPSD). While cholinesterase inhibitors are recommended in an attempt to delay memory loss and disability, what should be considered the most appropriate pharmacological treatment for BPSD has remained questionable. Antipsychotic medications, conventional and atypical agents, have been increasingly utilized in clinical practice but only a small number of clinical studies have investigated their relative cost–benefit ratio. This review focuses on the safety of atypical and conventional antipsychotics when used in patients with BPSD. Overall, atypical and conventional antipsychotics are associated with a similarly increased risk for all-cause mortality and cerebrovascular events. Relative to atypical agents users, patients being treated with conventional antipsychotics have an increased incidence of cardiac arrhythmias and extrapyramidal symptoms. Conversely, users of atypical antipsychotics are exposed to an increased risk of venous thromboembolism and aspiration pneumonia. Also, metabolic effects (i.e. increased risk of diabetes, weight gain) have consistently been documented in clinical studies with atypical antipsychotics, although this effect tends to be attenuated with advancing age and in elderly patients with dementia. Antipsychotics, both conventional and atypical, should be used with caution only when nonpharmacologic approaches have failed to adequately control BPSD. More effective interventions are necessary to improve postmarket drug safety in vulnerable populations.

Introduction

The progressive aging of the population is associated with a growing number of patients affected by dementia. At present time, in the United States, the prevalence of dementia is estimated to be around 20–30% among community dwelling individuals over 80 years, and up to 60–80% among elderly in nursing homes. This translates in about 4 millions of individuals currently affected by Alzheimer's disease only in the United States with a new case diagnosed every 72 s [1]. Thus, dementia is becoming a critical issue for any health care system, especially in western countries. Indeed, dementia causes progressive disability and it is an independent predictor of mortality. The expected lifetime for dementia patients is estimated to be between 5 and 12 years after the initial diagnosis [1]. Pharmacological treatment addresses two main clinical features: cognitive deterioration with predominantly memory loss and a constellation of disturbances referred to as “behavioural and psychological symptoms of dementia” (BPSD).

BPSD include hallucinations, delusions, agitation, wandering, aggression or abuse, but also apathy and anxiety. Virtually all patients with dementia will develop changes in behaviour and personality although nature and frequency of these symptoms might vary over the course of the disease [2]. BPSD are associated to an increased caregiver burden, an accelerated cognitive deterioration, earlier institutionalization and excess mortality [3].

Pharmacological treatment should be used only when nonpharmacologic approaches have failed to adequately control symptoms. Although different psychoactive medications including cholinesterase inhibitors, mood stabilisers, antidepressants and benzodiazepines may have some effect on distinct items of BPSD, antipsychotics are the only class of drugs which have shown the most consistent benefit in the treatment of BPSD [4], [5]. Antipsychotics are generally distinguished as either conventional or atypical [6]. Among conventional agents are classified haloperidol, thioridazine and several others phenothiazines, and butyrhophenones. All of these agents bind to the D2 dopaminergic receptor. Clozapine, risperidone, olanzapine and quetiapine have a receptor binding profile that is extremely more complex and heterogeneous and have been called atypical antipsychotics because supposedly devoid of extrapyramidal side effects.

Neither conventional nor atypical antipsychotics as class of drugs are approved for the treatment of BPSD. So, the use of these agents for this indication should generally be considered off-label, despite being endorsed by institution like the American Academy of Neurology. Only haloperidol and risperidone have received approval for the treatment of one or more symptoms of BPSD in over 30 countries [7].

Certainly, recent years have witnessed an increased utilization of antipsychotics and in particular of atypical agents. Studies among older patients living in long term care facilities have reported an increase in overall antipsychotic prescribing [8], [9], [10]. Other investigations have shown that atypical antipsychotics have become the most commonly prescribed antipsychotics [11]. In Italy, a drug utilization study has documented a 5-fold increased use of atypical agents for the treatment of BPSD between 1999 and 2002 [12].

In 2006, Ballard and Waite [13] completed a review for the Cochrane Collaboration concluding that risperidone and olanzapine have a modest efficacy in reducing aggression and psychosis. More recently, a meta-analysis of 7 studies on atypical antipsychotics (risperidone, olanzapine or quetiapine) documented neither a statistically nor a clinically significant difference in effectiveness compared to placebo [14].

These findings were confirmed by the initial report of the CATIE-AD (Clinical Antipsychotic Trials of Intervention Effectiveness Alzheimer's Disease) study which documented that the placebo group had significantly lower health costs than patients on risperidone, olanzapine or quetiapine [15], [16]. Additional analyses have explored clinical symptom changes in the four treatment groups among patients who continued the phase 1 treatment for up to 12 weeks. In this descriptive analysis of outpatients with Alzheimer's disease in usual care settings, some clinical symptoms improved with atypical antipsychotics. Antipsychotics may be more effective for particular symptoms, such as anger, aggression, and paranoid ideas. They do not appear to improve functioning, care needs, or quality of life [17].

With an unprecedented move, the manufacturer of risperidone in October 2002 notified all Canadian healthcare professionals that in drug-sponsored clinical trials, risperidone users had been found to have a higher rate of cerebrovascular events relative to those receiving placebo [18]. In March 2004, the UK Committee on Safety of Medicines through a Dear Doctor Letter [19] recommended avoiding atypical antipsychotic administration to elderly demented individuals with behavioural disturbances, particularly in those with a high baseline risk of stroke. At that time, information was reported only for olanzapine and risperidone although a similar alert was later released also by the manufacturer of aripiprazole [20].

On April 2005, an official warning was issued by the Food and Drug Administration (FDA)[21] to inform health professionals about the results of an independent, pooled analysis of 17 randomized clinical trials (RCTs). This reported a 1.7 times increased risk of all-cause mortality associated with atypical antipsychotic use in elderly persons with BPSD, compared to placebo. A similarly increased risk of death was documented with conventional antipsychotics use but FDA refrained from issuing a warning because data were based on only one trial with haloperidol.

These alerts have ignited a very animated debate in the scientific community. Some authors judged the warnings on atypical antipsychotics as unnecessarily alarming and potentially detrimental for patients with dementia [22]. Other researchers instead were concerned that there was no clear evidence to support a greater benefit with atypical relative to conventional antipsychotics [23]. The controversy has had an evident impact on prescription rates of antipsychotic medications among elderly patients with dementia. Although the warnings have slowed the growth in the use of atypical antipsychotics, they did not reduce the overall prescription rate of antipsychotics owing to a substitution with conventional agents. This has been documented to have occurred in Canada and in Japan [24], [25]. Since then several studies have been published which have consistently documented an even greater risk for all-cause mortality posed by the use of conventional antipsychotics in the treatment of elderly patients with BPSD. The controversy was finally set to rest on June 2008 when FDA required manufacturers of all conventional antipsychotics to warn about an increased risk of death associated with their off-label use in elderly patients with BPSD [26].

This review will critically evaluate the available data on the risks associated with the use of antipsychotics in elderly dementia patients with BPSD. We will consider as separate issues: all-cause mortality, cerebrovascular events, cardiac arrhythmias, pneumonia, venous thromboembolism, falls and fractures, metabolic abnormalities, extrapyramidal effects and hyperprolactinemia.

Section snippets

All-cause mortality

The initial suspicion came about in 2004 when, based on a pooled analysis of randomized clinical trials, the European Medicines Agency (EMEA) issued a warning about a 2-fold increased risk of all-cause mortality associated with olanzapine relative to placebo [27]. A more precise evaluation of the issue was based on the results of a meta-analysis which was independently completed and published in 2005 [21]. The meta-analysis included 17 placebo-controlled studies of four drugs (olanzapine,

Cerebrovascular events

A pooled analysis of RCTs has documented a nearly 3-fold increased risk for transient ischemic attacks (TIA) and stroke with risperidone and olanzapine, compared to placebo [40], [41], [42]. As a result, regulatory agencies have issued a warning which was extended to all atypical antipsychotics deeming the risk of cerebrovascular events (CVAE) a possible class effect.

Some authors have judged this alert as inappropriate first because of substantial uncertainty about the diagnostic accuracy of

Cardiac arrhythmias

Cardiac adverse events have been described for both atypical and conventional antipsychotics. The use of atypical antipsychotics may trigger sinus tachycardia, atrial and ventricular extrasystoles, and has been associated with rate-corrected QT (QTc) interval prolongation, T wave inversion, ST segment depression, and atrio-ventricular blocks [60]. Use of conventional antipsychotics has also been associated with an increased risk of ventricular arrhythmias, cardiac arrest, and sudden death [61],

Pneumonia

Infections, primarily pneumonia, have been listed as one of the most prevalent causes of death among elderly dementia patients enrolled in clinical trials on atypical antipsychotics. However, the reliability of that kind of information is highly questionable for the extraordinary competing risk of multiple conditions and because it was not required to obtain any specific information about the event.

In general, in elderly patients with dementia and/or psychiatric conditions the causal relation

Venous thromboembolism

A possible association between venous thromboembolism (VTE) and antipsychotic use was first suggested in the 1950s after the introduction of phenothiazines [89]. Since then, several case studies [90], [91], [92] have supported the notion of an increased risk of VTE with conventional antipsychotics. Recently, Zornberg and Jick [93] documented a 7-fold increase in the risk of idiopathic VTE among users of conventional antipsychotics who were younger than 60 years and free of major risk factors. A

Falls and fractures

A critical systematic review found that in 22 observational studies examining use of medications as a risk factor for falls in people aged ≥60 years, psychotropic classes, including benzodiazepines, antidepressants and antipsychotics, were associated with the highest risk [112]. Whether conventional and atypical antipsychotics confer a differential risk remains debated. A relatively small study of very short duration conducted among patients in residential care facilities in Australia has

Metabolic abnormalities

In patients with either schizophrenia or bipolar disorder use of antipsychotics has been associated with metabolic abnormalities including weight gain, lipid disturbances and altered glucose homeostasis, known risk factor for cardiovascular events [119]. Increased food intake is partly being held responsible for the weight gain in psychotic patients and is possibly a consequence of the antipsychotic drug's interaction with neuronal dopamine-, serotonin- and histamine-receptors [120].

Extrapyramidal effects

Conventional antipsychotics have been historically linked to a substantial incidence of extrapyramidal symptoms (EPS). The use of atypical antipsychotics is generally associated with a lower risk of EPS compared to conventional agents [127]. Different pharmacological mechanisms have been hypothesized including higher affinity for serotonin 5HT2A than dopamine D2 receptors, faster dissociation from D2 receptors, selective affinity for mesolimbic rather than nigrostriatal D2 receptors, partial

Hyperprolactinemia

Conventional antipsychotics may induce hyperprolactinemia by blocking dopamine D2 receptors on pituitary lactotroph cells, thereby removing the tonic inhibition on prolactin release provided by dopamine secreted by the tuberoinfundibular neurons in the hypothalamus [136]. With exception of risperidone and amisulpride, newer antipsychotics have a weak potential to cause elevation of plasma prolactin levels. Plasma prolactin increase is generally dose related and is more common in women, while is

Conclusions

Despite the growing number of elderly patients who will be affected by cognitive deterioration and BPSD in the future, critical aspects of the management remain unsolved [139]. Drugs should be used only when non-pharmacological approaches have failed to adequately control behavioral disruption. Despite there are substantial differences in the pharmacological properties between the two classes of antipsychotics, the most updated scientific evidence reviewed in this article seems to suggest that

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