Why are so few antipsychotic drugs licensed for Alzheimer’s disease related behavioral and psychological symptoms?

KEYWORDS:

• Alzheimer’s disease
• pharmacological therapy
• nonpharmacological therapy
• behavioral and psychological symptoms
• antipsychotic drugs
• safety

1. Summary

Alzheimer’s disease is the most common type of dementia. The progressive nature of the disease represents a challenge for clinicians, aiming to ensure an adequate treatment and support to the patient and the caregivers. Together with the impairment in several cognitive domains, progressively worsening, behavioral symptoms frequently occur. Among them, agitation and aggression pose great management difficulty; the therapeutic approach could be nonpharmacological and/or pharmacological. Unfortunately, even though the non-pharmacological approach is safer for the patient, the data about efficacy are sparse and limited. The pharmacological approach with antipsychotic drugs, together with heterogeneous results about efficacy, leads to higher rate of complications. For this reason, antipsychotic drugs are not licensed for the use in behavioral disturbances in dementia, apart from Risperidone; other drugs are usually prescribed off-label. All considered, the treatment of behavioral symptoms in dementia represents a great challenge for clinicians, especially when treating complex or frail patients.

2. Body of article

Dementia is a devastating group of cognitive diseases, affecting 50 million people worldwide; among those, Alzheimer’s disease (AD) on its own accounts for two thirds of the cases. This number is expected to increase and reach more than 150 million cases by 2050, as explained in the World Alzheimer’s report 2018. Apart from being a devastating disease, dementia implies huge social costs and resource consumption; in the United States, costs for AD are estimated to be about 1 trillion dollars per year [1]. Alzheimer’s disease is a neurodegenerative condition characterized by progressive decline in memory, impairment in language and executive functions, ability to solve problems and make coherent decisions, leading to a final loss of independency in the activity of daily living. Together with the cognitive symptoms, behavioral and psychological symptoms of dementia (BPSD) affect a huge percentage of demented subjects; more than 90% of people with dementia will experience BPSD within the course of the disease [2]. Around 20% of subjects without any BPSD at the diagnosis will develop some within 2 years [3]*. Those symptoms include aggression, agitation, apathy, depression, and lead to increased distress, for both patient and care givers, increased accesses to emergency departments and hospitalizations, with all the consequences on delirium and opportunistic infections, and impaired quality of life [2]. The onset of psychotic symptoms later in life is commonly related to dementing process; however, de novo psychiatric syndromes can occur in the older population, and the term ‘late paraphrenia,’ together with the issue about classification of old age insanities have been discussed for decades [4]. Several differences in symptoms and clinical manifestations have been highlighted between early and late onset schizophrenia [5]*, particularly important in the differential diagnosis with psychiatric symptoms in dementia. In patients with dementia, like AD, delusions of theft and paranoid disbeliefs of abandoning and mistrust are the commonest, and simpler than the ones in schizophrenia [6]*. They are likely due to impaired interpretation of reality because of the cognitive impairment instead of an actual psychotic symptom [7]*. Moreover, while a similar impairment in the inhibitory system has been found between AD and schizophrenia in the generation of hallucination, loneliness, and social isolation could be a more specific pattern in AD patients [8].

It is noteworthy that agitation and psychosis together are predictive of more rapid decline, increased institutionalization, and earlier death [9]. Thus, flourishing research has been conducted to find diagnostic features predictive for the development of psychotic symptoms in AD; even though a familial trend has been seen and a potentially inherited mechanism hypothesized, no clear genes have been identified yet [6]. Studies with neuroimaging techniques showed greater gray matter atrophy, reduced blood flow and glucose metabolism in AD with psychosis compared with subjects without psychosis, mainly localized in the neocortex rather than in the medial temporal structures [6]. An impaired balance between cholinergic and dopaminergic function, due to cholinergic loss, plays also a role in the delusional process in AD [10]. Thus, a range of medications – antipsychotics, benzodiazepines, cholinesterase inhibitors, memantine, anticonvulsants, and selective serotonin reuptake inhibitors – have been used to treat agitation in patients with dementia but have shown minimal efficacy and/or substantial adverse effects [9]. In this setting, the most recognized approach to behavioral symptoms is pharmacological and non-pharmacological, with the latter methodology usually preferred.

A recent meta-analysis evaluated different nonpharmacological interventions, such as sensory stimulation, cognitive and emotion-oriented interventions, behavioral management techniques, multicomponent interventions, exercise as well as animal-assisted therapy [3]. Music therapy showed some efficacy, particularly on agitation, aggressiveness, and to some extent anxiety, with some limitation due to the heterogeneity of the environmental, the music and the personal approach adopted [3]. Behavioral management and cognitive behavioral techniques have also been widely evaluated. In particular, behavioral management approaches aiming to improve communication skills, training of the caregiver as well as dementia mapping proved to be effective in agitation control, especially when supervised by a trained professional [3]. Multidisciplinary approaches showed efficacy in nursing home residents while, animal or exercise assisted therapy didn’t show any benefit on BPSD [3]. Pharmacological intervention for behavioral symptoms is greatly debated, due to safety reasons. First-generation antipsychotic drugs have been slowly replaced by second generation ones, having the latter less extra pyramidal side effects, and higher efficacy. Several studies have been carried out over the years, subsequently reviewed and summarized in meta-analyses, which proved the efficacy of antipsychotic drugs in reducing psychosis, aggression and agitation, sometime in a dose-dependent manner [11,12]**.

However, evidences have been brought up against the use of antipsychotic drugs, being associated with significant deleterious effects, such as increased risk of stroke, pneumonia, pulmonary edema, and mortality [13]. On top of these side effects, it has been demonstrated that patients using antipsychotic drugs have worst outcome in terms of independence, need of long-term care and institutionalization, even though the results are not homogenous. For these reasons, over the last few years a reduction in the prescription of antipsychotic drugs have been encouraged and pursued. Following the updates in the 2006 and 2011 NICE guidelines, in the United Kingdom a 19% reduction in the prescription have been recorded between 2009 and 2012 [13]. Unfortunately, the same trends have not been seen in other countries; in Italy, an increase of 7% have been recorded over the same time window, being especially high in nursing homes [13]. However, managing psychotic symptoms is extremely important in subjects with dementia, especially because cognitive decline is strictly linked to the risk of behavioral symptoms. In the majority of the studies evaluating this association, greater cognitive impairment was found in subjects with psychotic symptoms, compared to subjects without [14]. Moreover, in subjects developing psychotic symptoms, the cognitive decline has been demonstrated to occur more rapidly, even from the early phases of the disease, despite a similar level of impairment at baseline [14].

All taken together, clinicians are facing a great challenge, when managing patients with dementia and behavioral symptoms. On one hand, there is the burden of agitation or psychosis, greatly affecting every aspect of patients’ care and, on the other side there is the safety issue of the potential treatment drawbacks. Not less importantly, the caregivers’ quality of life has to be considered, especially for patients living in private accommodations, in order to make the management tolerable and reduce hospital admissions or institutionalization. In the United Kingdom, only Risperidone is licensed for the use in dementia patients, and only on a short-term basis, when the aggression determines increased risk for the patient; other antipsychotics are ‘off label,’ and every prescription has to be carefully considered.

A crucial aspect that also need to be evaluated is that, in most of the cases, AD patients are older thus, increasing the burden of comorbidity and poly-pharmacotherapy, with more chances of side effects and drug–drug interactions [15]. Overall, antipsychotic drugs have shown a very high risk in terms of safety, leading the FDA to the ‘black box’ warning, regarding mortality risk and a modest efficacy in managing symptoms. To date, great expectations are posed in the clinical trials for new drugs such as Pimavanserin, approved in the US for the treatment of psychotic symptoms like in Parkinson’s disease. The drug showed efficacy in AD associated psychosis in a phase 2 study, together with an acceptable tolerability, on a short term (6 weeks). Some improvement in agitation in AD has also been seen with serotonin and dextromethorphan/quinidine [16]**. Moreover, novel agents with varying mechanisms of action targeting behavioral and psychological symptoms associated with dementia are currently tested. Lumaterperone, a serotonin re-uptake inhibitor, is involved in a phase 3 trial ongoing since 2016, for the treatment of schizophrenia, agitation in dementia and depression in bipolar disease. Two other phase 3 trials are ongoing with Brexipiprazole, a dopamine receptor D2 partial agonist, approved in 2015 in USA for the treatment of depression and schizophrenia. Finally, the combination of Dextromethorphan and Buproprion, with a broad action and synergistic effects, is in phase 2–3 study, for the treatment of agitation and aggression in AD [16]**.

3. Conclusion

In conclusion, despite promising and interesting progresses in research of either useful biomarkers for early diagnosis or effective and safe drugs, BPSD in AD patients remain a complex burden of medical, social, economic, and emotional aspects, with several unknown variables and difficulties. Indeed, the complexity of AD is even higher when behavioral symptoms occur, and the safety issues related to the available drugs are hugely impacting on the management of AD patients. Given this premise, it seems difficult at the present time to give a certain treatment course. Future research with large appropriately powered studies using validated outcome measures for behavioral and psychological symptoms associated with dementia should be conducted to further establish the clinical utility of these agents. To date, a multimodal approach, combining non-pharmacological and pharmacological treatment seems to be appropriate, in order to reduce the risk at minimum, optimizing the results and success for the patients as well as the quality of life of caregivers.

Declaration of interest

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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.