Indications of atypical antipsychotics in the elderly

Abstract

Atypical antipsychotics (AAP) have become some of the most commonly prescribed medications in primary and specialist care settings. Off-label prescribing accounts for much of the expanded use of AAPs. This has become common in the elderly. Marketing by pharmaceutical companies appears to have contributed to the off-label use of AAPs, in situations where their safety and efficacy is far from established. Although evidence provides varying degrees of support for their use for behavioural and psychological symptoms of dementia, augmentation of antidepressants in depression, anxiety, insomnia and in the management of psychosis in Parkinson’s Disease, there are a number of potential problems with their expanded use in the elderly. These include weight gain, type two diabetes mellitus, sudden cardiac death and increased mortality rates in the elderly with dementia. It is recommended that whenever AAPs are used off-label, a review date is identified, informed consent is obtained and treatment and side-effects are closely monitored.

Keywords:

• atypical antipsychotics
• clozapine
• elderly
• indications
• off license
• olanzapine
• quetiapine
• risperidone

Indications of atypical antipsychotics in the elderly editorial

There is a disturbing paradox in the trend of atypical antipsychotic (AAP) prescribing in modern clinical practice. Psychosis and psychotic spectrum disorders are relatively rare in the general population, with a lifetime prevalence of approximately 2%. Yet AAPs, designed for the treatment of these conditions and licensed for few indications outside of psychosis, have become some of the most commonly prescribed medications in modern medicine.

There has been an estimated two- to five-fold increase in AAP use over the past 15 years [1,2]. Antipsychotic global sales were US$25.4 billion and the seventh biggest therapeutic group in 2010; Seroquel™ (quetiapine), Zyprexa™ (olanzapine) and Abilify™ (aripiprazole) were the 5th, 10th and 13th biggest selling pharmaceuticals, with sales of US$6.8; US$5.7 and US$5.4 billion, respectively [3]. Aripiprazole was the biggest selling medicine of any class in 2013 [4]. This has followed in the footsteps of quetiapine, which achieved the same feat in 2011 before its patent expired. The slow-release version of quetiapine has also been very successful in terms of sales with over a billion dollars in 2013 [4].

Studies examining the use of AAPs across specialist inpatient and outpatient populations and general practice indicate that between 43 and 70% of AAP use is off-label, and that this is particularly common in the young and elderly [2,5]. This unlicensed use has predominantly not been supported by scientific evidence [2,5,6]. Unpleasant extrapyramidal side effects, anticholinergic, antihistaminergic actions and cardiovascular risks arising from widening QTc interval appear to have largely limited the use of first-generation antipsychotic agents across all population groups, but more so in the elderly. The introduction of seemingly better-tolerated AAPs, with an apparently significantly decreased risk of extra pyramidal side effects contributed to the rapid expansion of AAP use for a wide variety of unlicensed conditions and in more diverse clinical populations. However, recent data from the large multicenter CATIE (schizophrenia treatment) study has challenged this assumption as it has shown that AAPs are no more effective or better tolerated than the predecessor first-line agents [7].

In addition, it is now also clear that pharmaceutical companies have influenced prescriber choices by vigorously promoting the prescription of AAPs (including direct to consumer advertising in the USA) to increase sales. They spent US$1.7 billion in 2007 and US$2.4 billion in 2010 doing so. Between 2007 and 2011, there was a particular focus on promoting aripiprazole (Abilify) and quetiapine (Seroquel) [8].

Pharmaceutical companies have also extended sales into unapproved diseases, unapproved disease subtypes and unapproved drug doses; a series of recent publications based on the analysis of whistleblower complaints and civil and criminal charges have exposed the use of systematic, sophisticated and far-reaching promotional methods, some of which may be resistant to external regulatory approaches [9]. An egregious but not unique example of a pharmaceutical marketing strategy aimed at promoting off-label use of AAPs in the elderly is that of Eli Lilly, who allegedly acted by ‘encouraging doctors who treated people in nursing homes and assisted care facilities to prescribe olanzapine, because one of the drug’s side effects is sedation’ and ‘this side effect was a therapeutic benefit, not an adverse event.’ The sales force used the slogan ^‘5 at 5,’ meaning that 5 mg of olanzapine at 5 pm would help patients sleep’ [10–12].

Prescribing AAPs in the elderly can be particularly problematic, as they are more susceptible to side effects, and there is significantly more potential for adverse drug interactions in a population often exposed to polypharmacy.

There are limited options for the treatment of behavioral and psychological symptoms of dementia (BPSD). AAPs are commonly prescribed for BPSD, although the effect sizes are small (<0.2 standard deviations of difference between treatment and control groups), and important differences are seen in both the benefits and adverse effects across agents [13]. There is evidence to support the use of olanzapine and risperidone for agitation and risperidone alone for psychosis associated with dementia [14,15]. Risperidone is licensed for the treatment of BPSD in New Zealand, Canada, Great Britain and Australia, but is not licensed for this in the USA. No other antipsychotic is licensed for this indication.

It is important to note that in elderly patients with dementia, AAPs are associated with an increased risk of pneumonia, cerebrovascular adverse effects, sedation, hip fractures and extrapyramidal side effects [14,16,17]. The DART-AD trial has shown that long-term use of antipsychotics for BPSD is associated with increased mortality compared to placebo [18]. In the elderly, there are differences in the relative mortality risk between AAPs and the risk is dose related. It is particularly noteworthy that olanzapine and risperidone have been shown to increase the risk of death when compared to placebo (number needed to harm = 87), and risperidone is associated with an increased risk of stroke (number needed to harm = 53) [13]. There is an increased risk of death with higher doses of risperidone and olanzapine, and after adjustment for dose, olanzapine and quetiapine have a lower mortality risk than risperidone [19]. Conversely AAPs have been found to decrease mortality following long-term cumulative exposure in their original licensed indication schizophrenia [20] (in an adult rather than elderly population). Although the introduction of ‘black box warnings’ in 2005 led to a decrease in the use of AAPs in dementia, they remain fairly popular agents, prescribed in 9–12% of these patients [21,22].

Of the AAPs, quetiapine, in particular, is commonly prescribed for anxiety, agitation and night sedation, as an alternative to benzodiazepines. These are symptoms that commonly affect the elderly. The use of quetiapine does have some appeal, as there is evidence to suggest that quetiapine has efficacy for these symptoms [15,23–26], but it must be noted that its use can lead to significant short- and long-term side effects, which include sedation (potentially beneficial depending on the indication it is used for), weight gain (even at low doses), type two diabetes mellitus, raised lipids and sudden cardiac death [14,27–29].

Depression is common in the elderly. The use of AAPs to augment antidepressants in depression when there has been insufficient response to an antidepressant alone is a popular strategy. Aripiprazole, olanzapine and quetiapine are licensed for this indication. There is evidence to support risperidone augmentation, even though this is not currently a licensed indication [15]. Although there is evidence to support quetiapine as monotherapy in depression, the US FDA declined to license quetiapine as monotherapy due to concerns around exposing a large population to its metabolic adverse effects [30]. There is a risk that non-specialist prescribers (particularly in primary care), who are less well acquainted with the side-effect profile of AAPs, may expose patients to significant reversible and irreversible short- and long-term extra pyramidal and metabolic side effects, particularly as these agents are increasingly utilized for the augmentation of antidepressant treatment in depression.

There is a role and efficacy for off-label clozapine use in the management of psychosis in Parkinson’s disease, with minimal exacerbation of the motor symptoms [31]. However clozapine’s significant adverse effect profile, multiple medication interactions and mandatory blood monitoring limit its use for this indication. The evidence base for other AAPs is weak [14].

Given the high prevalence of psychiatric and neuropsychiatric disorders associated with ageing, and the significant ageing population structure in Asian and Western countries, the use of AAPs is likely to increase in the foreseeable future. A significant proportion of this will be prescribed off-label. The use of AAPs in this population group is associated with adverse outcomes, including a small but statistically significant increased risk of death in elderly patients with dementia. In this context, it is imperative that greater emphasis is given to research in this area, in particular to determine the long-term efficacy and safety in the management of BPSD. Moreover, given the apparent popularity of quetiapine in the managements of agitation, anxiety and insomnia in this age group, head-to-head trials with other effective treatments such as benzodiazepines and SSRIs to establish efficacy and safety would be desirable.

However, given the risks associated with AAPs in this population and the limited evidence for their efficacy, in our opinion it is unlikely that the pharmaceutical industry will pursue licensing extensions to include these common conditions in the elderly. In addition, the high persisting prevalence of off-label AAP prescribing suggests that licensing constraints do not significantly limit prescribing habits and the sale of these medicines.

For any treatment intervention, proven benefits define the parameters of acceptable risks; it is therefore incumbent on the prescriber to ensure that the benefits of AAP treatment outweigh their risks. In most instances, this has not been established with any degree of clinical certainty. However, clinical situations do arise where the use of these agents in the elderly can be helpful and needs to be considered. We recommend that whenever AAPs are used off-label, informed consent is obtained, treatment and side-effects are closely monitored, and an end- or review point of treatment is identified.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.