pharmaceuticals
Review
Behavioral and Psychological Symptoms in Dementia (BPSD)
and the Use of Antipsychotics
Valeria Calsolaro 1 , Grazia Daniela Femminella 2 , Sara Rogani 1 , Salvatore Esposito 2 , Riccardo Franchi 1 ,
Chukwuma Okoye 1 , Giuseppe Rengo 2,3 and Fabio Monzani 1, *
1
2
3
*
Citation: Calsolaro, V.; Femminella,
G.D.; Rogani, S.; Esposito, S.; Franchi,
R.; Okoye, C.; Rengo, G.; Monzani, F.
Behavioral and Psychological
Symptoms in Dementia (BPSD) and
the Use of Antipsychotics.
Pharmaceuticals 2021, 14, 246.
https://doi.org/10.3390/ph14030246
Geriatrics Unit, Department of Clinical & Experimental Medicine, University of Pisa, 56126 Pisa, Italy;
v.calsolaro@ao-pisa.toscana.it (V.C.); sara_rogani@hotmail.it (S.R.); riccardo.franchi@me.com (R.F.);
chukwuma.okoye@phd.unipi.it (C.O.)
Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples,
80138 Naples, Italy; graziadaniela.femminella@unina.it (G.D.F.); salvatorespositomed@gmail.com (S.E.);
giuseppe.rengo@unina.it (G.R.)
Istituti Clinici Scientifici Maugeri SpA Società Benefit, Via Bagni Vecchi, 1, 82037 Telese, Italy
Correspondence: fabio.monzani@med.unipi.it; Tel.: +39-333-773-3135
Abstract: Dementia affects about 47 million people worldwide, number expected to exponentially
increase within 30 years. Alzheimer’s disease (AD) is the most common dementia type, accounting
on its own for almost 70% of all dementia cases. Behavioral and psychological symptoms (BPSD)
frequently occur during the disease progression; to treat agitation, aggressiveness, delusions and
hallucinations, the use of antipsychotic drugs should be limited, due to their safety issues. In this
literature review regarding the use of antipsychotics for treating BPSD in dementia, the advantages
and limitation of antipsychotic drugs have been evaluated. The available medications for the
management of behavioral and psychological symptoms are the antipsychotics, classed into typical
and atypical, depending on their action on dopamine and serotonin receptors. First generation, or
typical, antipsychotics exhibit lack of tolerability and display a broad range of side effects such as
sedation, anticholinergic effects and extrapyramidal symptoms. Atypical, or second generation,
antipsychotics bind more selectively to dopamine receptors and simultaneously block serotonin
receptors, resulting in higher tolerability. High attention should be paid to the management of
therapy interruption or switch between antipsychotics, to limit the possible rebound effect. Several
switching strategies may be adopted, and clinicians should “tailor” therapies, accounting for patients’
symptoms, comorbidities, polytherapies and frailty.
Academic Editor: Damian Holsinger
Received: 24 January 2021
Keywords: dementia; behavioral and psychological symptoms of dementia (BPSD); atypical antipsychotics; typical antipsychotics; frailty
Accepted: 4 March 2021
Published: 9 March 2021
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1. Introduction
The term “dementia” refers to a clinical syndrome characterized by progressive cognitive decline that interferes with independence in everyday activities. According to the
Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV, dementia is defined
as a decline in memory and impairment in at least one other cognitive domain, such as
executive function (e.g., planning, attention and abstract reasoning), language, visuospatial
skills, praxis or judgment. Symptoms of dementia are gradual, persistent and progressive.
Alongside the symptoms that affect cognitive functions, there are alterations in personality
and behavior, such as agitation, apathy, aggression, psychosis, hallucinations and delusions;
their clinical presentation varies greatly among individuals and can cause considerable
distress for patients and their caregivers [1]. Alzheimer’s disease (AD) is the most frequent
cause of dementia [2]. Other common causes of dementia include vascular dementia, dementia with Lewy bodies (LBD), frontotemporal dementia (FTD) and Parkinson’s disease
dementia (PDD). There are also rare forms of degenerative brain diseases that can cause
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dementia, like progressive supranuclear palsy (PSP), cortical basal degeneration (CBD),
multisystemic atrophy (MSA), Huntington’s disease (HD) and Creutzfeldt-Jakob disease
(CJD) [3]. Mixed Vascular–Alzheimer Dementia (MVAD) consists in the simultaneous
presence of Alzheimer’s disease and cerebrovascular disease (CVD); it is quite common in
older patients, with a prevalence of around 22% [4]. Eventually, almost 10–15% of patients
with cognitive impairment may have a reversible cause, if treated in time and correctly,
like endocrine diseases, normal pressure hydrocephalus, depression and drug-induced
dementia. Dementia is an increasingly common phenomenon due to the aging population,
and a major global public health challenge; its prevalence is expected to exponentially
increase within the next 30 years [5]. Nevertheless, a recent meta-analysis of age-specific
incidence of dementia and AD found that incidence rates of dementia have declined over
the last four decades, but AD incidence rate actually increased for younger age groups in
non-Western countries [6]. Behavioral and psychological symptoms of dementia (BPSD)
represent a heterogeneous group of affective, psychotic and behavioral symptoms that
occur in the majority of patients with dementia, causing great suffering and increasing the
caregivers’ burden [7]. In this review, we evaluate the use of antipsychotic drugs in dementia. The search was conducted in PubMed, with the keywords “Dementia, Alzheimer’s
Disease, antipsychotic and Dementia/Alzheimer’s disease, BPSD, behavioral and psychological symptoms dementia, risperidone, quetiapine, haloperidol, aripiprazole, olanzapine,
antipsychotics tapering, antipsychotics switch, typical/atypical antipsychotics”; metaanalysis, reviews and original works and abstracts in English have been selected and
reviewed, published within the last 10 years.
2. Behavioral and Psychological Symptoms of Dementia (BPSD)
BPSD are among the earliest signs and symptoms of neurocognitive disorders and cognitive decline and, although they fluctuate, their severity exponentially increases over the
course of the disease. Neuropsychiatric symptoms are associated with several negative outcomes, such as faster cognitive decline, functional impairment, reduced independence and
inability to complete activities of daily living, with progression to more severe stages of dementia and increasing risk for secondary complications such as falls and fractures, causing
higher hospitalization rates and eventually early institutionalization [8]. The etiopathogenesis of BPSD is complex as it is probably the result of the interaction of multiple factors,
such as biological (brain changes, comorbidities, medications), psychological (personal
life history, personality) and social factors (support network, living arrangements) [8]. In
their review, Eissa et al. examined the hypothesis that chronic neuroinflammation may be
associated with cognitive deficits, and found that central histamine (HA) plays a significant
role in the regulation of neuroinflammatory processes of microglia functions in numerous
neuropsychiatric diseases such as BPSD [9]. In a meta-analysis by Qing-Fei et al., apathy
resulted as the most common neuropsychiatric symptom reported in the Neuropsychiatric Inventory (NPI), followed by depression, aggression, anxiety, sleep disturbances,
irritability, change in appetite, motor problems, hallucinations, delusions, disinhibition and
euphoria [10]. Psychiatric symptoms like depression, irritability, agitation in cognitively
normal subjects may also be predictors of possible more rapid cognitive decline. In their
study, Banks et al. assessed the relationship between behavioral symptoms and emergence
of mild cognitive impairment or dementia in older adults, over a 4-year period. The results
suggested that anxiety and depressed mood moderately increased the risk of developing
dementia, primarily Alzheimer’s disease, representing precursors to future cognitive decline [11]. The relationship between depressive symptoms and cognitive decline appears
to be complex; whether depression is a very early manifestation of Alzheimer’s disease or
increases susceptibility to it remains to be determined. Nevertheless, a large longitudinal
study of people aged 50 to over 90 years showed that depressive symptoms were associated
with a slight acceleration in cognitive decline in people aged 60–80 years, but there was no
support for the hypothesis that there might be a bidirectional connection between depression and AD [12]. Different BPSDs are often co-present and can be clustered into distinct
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domains, suggesting that they should be considered as groups of symptoms rather than
lonely symptoms, with each group reflecting a different prevalence, timeline, biological
and psychosocial correlates. During the last few decades, several studies have been conducted with the aim of identifying possible AD sub-syndromes defined by combinations
of different neuropsychiatric symptoms. Most of these studies included only patients with
AD, whereas others included patients with various dementia subtypes. In their study,
Canevelli et al. identified three clusters of symptoms: 1—“psychotic” cluster (“delusions”
and/or “hallucinations” items); 2—“emotional” cluster (“agitation/aggression” and/or
“depression/dysphoria” and/or “anxiety” and/or “irritability” items); and 3—“behavioral”
cluster (“euphoria/elation” and/or “apathy” and/or “disinhibition” and/or “aberrant
motor behavior” items) [13]. The study showed no statistically significant impact of different neuropsychiatric sub-syndromes on the rate of cognitive decline, indicating that the
cognitive progression of dementia seems to be scarcely affected by the presence of specific
clusters of symptoms [13]. Thompson et al. examined the associations between dementia
subtypes, severity of dementia and severity of BPSD. They found that severity of BPSD did
not differ between AD and vascular dementia, but was higher in those patients with greater
severity of dementia [14]. Considering that different behavioral symptoms belonging to
different clusters are often co-presenting, the idea that there could be a common underlining neurotransmitters disruption may arise. Monoamine 5-hydroxytryptamine (5-HT), or
serotonin, is one of the most important neurotransmitters in the central nervous system
(CNS), regulating multiple physiological functions. 5-HT works as both a neurotransmitter
and neuromodulator, acting in both central and peripheral systems. Serotonergic circuitry
has been tied to cognitive decline and implicated in a number of basal and higher brain
functions that are perturbed in BPSD. It is highly possible that the co-clustering of BPSD
into domains depends on different circuits via diverse expression of 5-HT receptor subunits [15]. Dopaminergic system as well is involved in behavioral disturbances genesis
and control. Dopamine (DA) is not only fundamental for motor control, due to the activity
within the basal ganglia, but is also responsible for the processing of cognitive information,
perception and adaptation to the environment [16].
3. Antipsychotic Use in Dementia
Antipsychotics represent the main pharmacological strategy to alleviate BPSD, improving the quality of patients’ and caregivers’ lives [17]. Despite the warnings issued
by the US Food and Drug Administration (FDA), the European Medicines Agency and
the UK Medicines and Healthcare Products Regulatory Agency, antipsychotics are often
used in individuals with dementia for sustained periods (≥6 months) [18,19], although
they are associated with increased risk of death, cerebrovascular adverse events (CVAEs),
Parkinsonism, sedation, gait disturbance, cognitive decline and pneumonia [20]. This
risk remains elevated for at least 2 years, with an increased number of deaths due to
antipsychotics prescription and longer duration of use. A recent meta-analysis including
several large retrospective studies showed an increased all-cause mortality associated with
antipsychotic use in patients with dementia [21]. Nevertheless, these drugs have been
increasingly prescribed over the last several years, even for long-term use. Amongst antipsychotics, only risperidone is indicated for the short-term management of persisting and
severe aggression in individuals with AD who have failed non-pharmacological trials [22].
Off-label treatment with antipsychotic medications has grown in the past two decades,
with increasing prescription rates, estimated to be between 20% and 50% [23], and is even
higher among institutionalized individuals with dementia [24]. Given that, the importance
of the careful evaluation of the potential drug–drug interactions between antipsychotics
and Ache-I or memantine, especially in a population of older patients often affected by
several chronic diseases and undertaking polytherapy, becomes clear [25]. The complex
management of BPSD requires a deep knowledge of antipsychotics’ mechanism of action,
possible pharmacological interactions, symptoms overlapping and spectra, without overlooking the social context, the patient and caregiver counselling and always considering
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a non-pharmacological therapy as a first approach. The most relevant literature for the
possible mechanism of action of antipsychotic drugs derives from studies in schizophrenia
and mania; even though it is possible to apply them to a geriatric population from a purely
pathophysiological point of view, it is mandatory to fully assess the older and often frail
demented patient, in order to minimize adverse events or drug–drug interactions.
Antipsychotics are commonly classed as either typical or atypical based upon their
potency as dopamine D2 receptor antagonists and their actions on serotonin 5-HT2A receptors [26]. While several studies, such as the National Institute of Mental Health (NIMH),
Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and sub-studies have
not demonstrated a clear and significant difference between second and first generation
antipsychotics, at least for schizophrenia, their better safety profile, particularly for extrapyramidal symptoms (EPS), would grant them some actual advantage [27].
3.1. Typical Antipsychotics: Mechanisms and Limitations
Based on their chemical structures, they are grouped into several classes: phenothiazines (e.g., chlorpromazine and fluphenazine), butyrophenones (e.g., haloperidol), benzamides (e.g., sulpiride and tiapride), and were developed mainly for the treatment of
schizophrenia, with the first agents licensed in the 1950s. Since their discovery, first
generation antipsychotics have been the standard for treating psychotic disorders for
many decades. These classical neuroleptics or typical antipsychotics display a rather
narrow spectrum of therapeutic activity, however, and because of their wide receptor
profile, their use is associated with several side effects. Since they bind predominantly
to D2 receptors throughout the brain as powerful, long-lasting antagonists, as well as to
a broad range of other receptors, including D1, 5-HT2, histamine H1 and α2 adrenergic
receptors [26], they lack the tolerability of newer antipsychotics, inducing, among others,
sedation, anticholinergic effects and EPS. Haloperidol is now the most widely prescribed
agent from this category, mainly because it is considered a first-line treatment in hypoactive,
hyperactive and mixed type delirium, according to NICE guidelines [28]. Haloperidol
preferentially binds dopamine receptors (in particular, D2, D3 and D4) and α1 adrenergic
receptors, while it has negligible affinity for H1, M1 and 5-HT (in particular, 5-HT 2C)
receptors [26]. Although a recent study [29] reported that the number needed to harm
(NNH) with haloperidol for the outcome of mortality was similar to risperidone, another
more recent study evaluating community dwelling AD patients’ mortality documented
a higher mortality risk in patients treated with haloperidol compared to quetiapine or
risperidone [30]. When a diagnosis of dementia was not required for inclusion, risk of
both death and femur fracture in nursing home residents was higher for conventional
antipsychotics compared with atypical antipsychotics [31]. Recently, a large retrospective
study conducted on a population of patients with newly diagnosed dementia evaluated
the impact of antipsychotic medications on acute cerebral and cardiovascular events, hip
fracture and venous thromboembolism [32]. The use of antipsychotic drugs appeared to
be associated with increased risk of stroke, thromboembolism and hip fracture, while no
increased risk was detected regarding long-term mortality [32]. In addition, a more recent
systematic review of 36 Randomized Clinical Trials (RCTs) compared the efficacy of risperidone, haloperidol, SSRI as a class and dextromethorphan/quinidine in treating agitation
in people affected by all-types dementias; the results showed that haloperidol was almost
the least efficacious among all comparators, dissuading prescription of this medication in
this particular case [33]. Lastly, the American Psychiatric Association (APA) recommends
that in the absence of delirium, if nonemergency antipsychotic medication treatment is
required, then haloperidol should not be used as a first-line agent (Recommendation 1B).
Furthermore, the APA recommends that in individuals with dementia and agitation or
psychosis a long-acting injectable antipsychotic medication should not be utilized unless
it is otherwise indicated for a co-occurring chronic psychotic illness (Recommendation
1B) [34].
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3.2. Atypical Antipsychotics: Mechanisms and Advantages/Limitations
Atypical antipsychotics include clozapine, risperidone, olanzapine, quetiapine and
aripiprazole. They comprise serotonin and dopamine antagonists (SDAs), multiple-acting
receptor targeted antipsychotics (MARTAs) and dopamine D2 partial agonists [35].
It must be noted, however, that these second generation antipsychotics (SGA) target a
broader range of receptors with different affinity. In general, they not only exert antagonist
effect on dopamine D2, but also have a simultaneous antagonist effect on 5-HT receptors,
particularly on the 5-HT2A ; this results in increased blockage efficacy on the mesolimbic
pathways, but not on the nigrostriatal one [26].
However, different potency of affinity splits them into a group of drugs with modest
affinity for D2, 5-HT2A and other receptors such as H1 and M1 (clozapine, olanzapine and
quetiapine) and those with potent antagonist action on D2 and 5-HT2A , high affinity for α1 ,
5-HT2c and H1 and negligible affinity for M1 receptors (risperidone, paliperidone, lurasidone) [26]. Clozapine has become the prototype for new neuroleptics, due to its favorable
receptor profile and low incidence of Parkinsonism and tardive dyskinesia; however, the
increased risk for agranulocytosis, weight gain and metabolic alterations had a negative
impact on its use. Risperidone, with higher affinity for 5-HT2A than for D2, has shown good
efficacy in treating positive symptoms and increased dopaminergic neurotransmission in
the nigrostriatal pathway with reduced EPS [36]. However, the strong binding to 5-HT2C ,
α1 and H1 is responsible for the side effects, such as weight gain, sedation, orthostatic
hypotension [26]. The higher affinity for different target receptors justifies the possible
different or added desired or adverse effects of the different drugs. In particular, affinity to
histamine-1 receptor is higher for olanzapine and quetiapine, to 5HT-51C for risperidone,
clozapine and olanzapine, to adrenergic receptor for clozapine, quetiapine, olanzapine (α1
and α2) and risperidone (α2) [37]. A further improvement in their mechanism of action led
to the development of a third generation of antipsychotics. Often referred to as dopamine
system stabilizers (DSSs), they act as partial D2, D3 and 5-HT1A -receptor agonists, and
antagonists at 5-HT2A receptors. In other words, they can act either as a functional agonist
or a functional antagonist, depending on the surrounding levels of dopamine. The antipsychotic action would follow the functional antagonism in the mesocortical pathway, where
excess of dopamine causes positive symptoms, while the action as functional agonist in
the mesocortical pathway improves the negative symptoms [38]. Reliant on local levels of
dopamine, DSSs do not cause motor side effects, preserving dopamine activity in those
regions where normal dopamine levels are needed (nigrostriatal pathway) [26]. Aripiprazole may be considered representative of this latter group of neuroleptics, with its reduced
association with extrapyramidal side effects and its efficacy against both positive and
negative symptoms of schizophrenia. Aripiprazole causes minimal weight gain, sedation
and does not produce elevation in serum prolactin levels; most importantly, unlike other
neuroleptics, it does not lengthen QTc interval on electrocardiogram [39]. Nonetheless,
atypical neuroleptics account for >80% of the neuroleptics prescribed for people with
dementia, and the most widely prescribed are risperidone, olanzapine and quetiapine. Several studies compared first generation antipsychotics (FGA) and SGA safety profile. In 2014,
the increased risk of cardio and cerebral vascular events (stroke, ventricular arrhythmia,
myocardial infarction), as well as hip fractures, has been highlighted [40]. Almost 10% of
strokes and hip fractures were more frequent in the group treated with FGAs, whereas the
difference in the two groups was lower for myocardial infarction and ventricular arrhythmia. Combining these data, all the adverse events accounted for approximately one sixth
of the mortality differences between FGAs and SGAs, even though this difference could
be as large as 42% [40]. Recently, a systematic review analyzed a total of 16 meta-analyses
evaluating the use of antipsychotics in individuals with dementia; of those, only two were
specifically focused on AD, one on LBD and the others more generically on dementia. The
authors did not find any evidence in the evaluation of the difference in mortality rates between first and second generation antipsychotics (FGAs and SGAs) in older adults [41]. In
particular, 10 meta-analyses evaluated atypical antipsychotics and only two meta-analyses
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evaluated typical antipsychotic medications. When used in individuals with dementia,
including AD, atypical antipsychotic medications, especially quetiapine, showed modest
efficacy. Greater responses to atypical antipsychotics were observed in individuals with
severe psychosis, aggression and agitation, whereas smaller effects were noted for subjects
with less severe symptoms. Furthermore, in these 10 meta-analyses, antipsychotics use in
individuals with dementia was associated with a greater number of adverse effects when
compared with individuals treated with placebo, including the risk of CVAEs and death.
In comparative effectiveness studies of second generation antipsychotics, risperidone
was superior to quetiapine in the Cohen-Mansfield Agitation Inventory (CMAI) [42]. The
effectiveness of quetiapine is considerably weaker than risperidone. Nevertheless, a metaanalysis involving five randomized trials observed a statistically significant effect relative
to placebo on neuropsychiatric symptoms, as evaluated with the NPI and overall improvement (Clinical Global Impression (CGI) scores) [43]. Moreover, quetiapine could be the
antipsychotic of use to treat BPSD in patients with Parkinsonian features, thanks to the
lower induction of extrapyramidal signs [8]. Aripiprazole shows a weaker effectiveness
than risperidone as well. Moreover, aripiprazole showed better outcome, compared to
placebo, in NPI, Brief Psychiatric Rating Scale (BPRS) and Cohen-Mansfield Agitation
Inventory (CMAI), while olanzapine, quetiapine and risperidone did not [42]. Even though
atypical antipsychotics have a better safety profile, they may present with several adverse
events, such as anticholinergic effects, orthostatic hypotension, seizures, metabolic syndrome, weight gain, extrapyramidal symptoms, sedation and QT-prolongation [8]. Another
important finding is the increased risk of stroke and mortality associated with the use of
atypical antipsychotics [44].
Notwithstanding the slight advantage of second upon first generation antipsychotics,
in the recent network meta-analysis pooling together studies mainly on dementia, but also
including mixed and one study comprising LBD, no atypical antipsychotic was consistently
associated with better results than the others across all effectiveness and safety outcomes,
risk of death included [42].
All these data suggest the importance of being cautious with the prescription of
antipsychotics, particularly in frail patients, where the increased risk of hip fracture or
cardiovascular events might accelerate or worsen the loss of independence, increase the
hospitalization and the global outcome as well as the cognitive impairment. An accurate
medical history and global comprehensive medical assessment would reduce the inappropriate prescription of drugs such as olanzapine or risperidone in patients with high
cardiovascular risk or cerebral ischemia, as suggested also by the American Psychiatric
Association guidelines and STOPP/START criteria.
4. Antipsychotic Therapy: Management Issues and Drugs Switch
The first issue for geriatricians having to treat BPSD in patients with dementia is the
non-optimal risk/benefit balance of antipsychotics use in these patients. Unfortunately,
however, the incidence of psychiatric symptoms is high and the need for treatment to
manage patients and caregivers, avoiding inappropriate hospital admission and further
functional and cognitive decline, becomes clear. It must be highlighted that only two
drugs are licensed for BPSD treatment in dementia: pimavanserin for hallucinations and
delusions associated with Parkinson’s Disease (PD) psychosis (USA), and risperidone for
short-term treatment of persistent aggression in moderate-to-severe AD (only in Canada
and UK). In the remaining cases, the use of antipsychotics is off-label and guided by the
physician’s judgment [45].
A glance at the real word shows that up to 60% of patients with cognitive impairment
in hospitals and long-term care homes are being treated with antipsychotics for neuropsychiatric symptoms related to dementia and AD [46]. The majority of the antipsychotics
administered are the atypical ones. These drugs, especially risperidone, aripiprazole and
olanzapine, have been evaluated in multiple studies and show improvement in symptoms
like severe agitation, aggression and psychosis (such as delusions and hallucinations) in
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patients with dementia [41]. Risperidone and aripiprazole are the most employed drugs
in BPSD and they are effective in the treatment of psychotic symptoms, agitation and
aggression [47,48].
The incidence of side effects observed in previous studies, the poor tolerability and the
increased risk of mortality related to the antipsychotic therapy demand further research [46].
The second issue for clinicians is the choice of the right drug and therapy-tailoring; as
a general guideline, it is desirable to use antipsychotics in the lowest dose sufficient to
control symptoms, for the shortest duration, with close monitoring for the development
of adverse effects [49]. Moreover, regular clinical evaluations of risks and benefits are
necessary during the treatment [34]. To decrease the risks mentioned above, physicians
should consider gradual tapering off of antipsychotics once control of behavioral symptoms
is achieved, although there is limited evidence regarding patient outcomes after stopping
antipsychotics [49] and insufficient evidence to indicate whether discontinuation impacts
on mortality or other side effects associated with antipsychotics [50]. As underlined in a
recent Cochrane, the evidence that the interruption of long-term antipsychotic therapy in
older patients with dementia may be done without worsening of symptoms is limited; in
particular, higher benefit may be seen in patients with milder symptoms [50].
To facilitate the process of tapering off the medication, Tjia et al. proposed a gradual
reduction of the dose of the antipsychotic in two steps based on pharmacokinetic principles
that favor drug discontinuation [51]. A small study of 36 patients suggested that the
use of citalopram may facilitate the withdrawal of antipsychotics for the elderly with
AD [52]. The Halting Antipsychotic Use in Long-term Care (HALT) study was a single-arm
longitudinal study conducted in Australian long-term care facilities among patients taking
antipsychotics, 98.5% of whom had dementia. Of the 93 patients who completed the study,
69 (74%) had antipsychotics successfully deprescribed without reinitiating antipsychotics
or experiencing increase in BPSD [53]. A question of primary importance, relating to the
use of these molecules, is the management of the switch from one antipsychotic to another.
There are essentially two reasons that can lead a clinician to program a switch: suboptimal
efficacy of a drug, resulting in the need to switch to a different drug, or appearance of
unacceptable side effects for the doctor and/or the patient, associated with a reduction
in adherence to therapy and a risk of potential relapse. The transition between different
antipsychotics can often be associated with the onset, albeit transient, of unwanted clinical
manifestations. In particular, if the switch is not done correctly, unwanted effects due to the
rebound effect and withdrawal symptoms can occur [54]. The risk of rebound side effects
is particularly high following abrupt discontinuation of a short half-life antipsychotic and
replacing it with a longer half-life antipsychotic. The likelihood of rebound and withdrawal
effects is greater when the two antipsychotics (pre- and post-switch) differ from each other
in their pharmacodynamic profile (pharmacodynamic rebound) or when the half-life of the
pre-switch antipsychotic is particularly short (pharmacokinetics rebound).
Pharmacokinetic rebound occurs when the post-switch antipsychotic is relatively
underdosed, that is, when its plasma levels are not sufficiently high to achieve a degree of
functional receptor blockage similar to that obtained by the pre-switch drug. In clinical
terms, the outcome of pharmacokinetic rebound is identical to that of pharmacodynamic
rebound. In general, the lower the half-life of an antipsychotic that must be discontinued
and replaced with another antipsychotic, the greater the risk of pharmacokinetic rebound
effects upon its abrupt withdrawal, especially if the second drug has a longer half-life [55].
A pharmacodynamic rebound occurs when patient’s receptors, previously exposed for a
prolonged period to a blocking action by a specific antipsychotic, with consequent effect of
upregulation, suddenly find themselves exposed to the endogenous ligand for that type
of receptor. This can occur when an antipsychotic is interrupted or abruptly switched to
another one with less affinity towards that same receptor system. The rebound effects
experienced by the patient are generally opposite to those attributable to the receptor block.
The rebound following the suspension of dopaminergic drugs is due to hypersensitivity to endogenous dopamine, and the patient might present either with psychosis or
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supersensitivity mania due to the effect on the mesolimbic system, or with rebound dyskinesia due to the effect on the nigrostriatal system [56]. The histaminergic rebound effect
usually follows the abrupt withdrawal of an antipsychotic with a potent histaminergic
blocking action, as in the case of chlorpromazine, clozapine, quetiapine and olanzapine.
Since the blockage of the H1 is associated with anxiolytic, sedative effect, sleep induction, increased appetite and weight, an abrupt discontinuation of one of the previously
mentioned antipsychotics could lead to the onset of agitation, anxiety and insomnia [54].
Finally, the cholinergic rebound occurs in cases of discontinuation of an antipsychotic with
cholinergic blocking action, such as clozapine, olanzapine and quetiapine. The abrupt transition, followed by excessive stimulation of the central M1 receptors, can trigger rebound
symptoms such as agitation, insomnia, mental confusion, psychosis, anxiety, drooling,
EPS/akathisia together with diarrhea, sweating, nausea, vomiting [55]. Table 1 shows the
possible rebound symptoms when interrupting a drug, depending on specific receptors’
blockage release.
Table 1. Possible rebound symptoms when interrupting an antipsychotic drug.
Receptor
Possible Rebound/Withdrawal Effects
D2
a1 -adrenergic
a2 -adrenergic
H1
Psychosis, mania, agitation, akathisia, withdrawal dyskinesia
Tachycardia, hypertension
Hypotension
Anxiety, agitation, insomnia, restlessness, EPS/akathisia
Agitation, confusion, psychosis, anxiety, insomnia, sialorrhea,
EPS/akathisia
Diarrhea, sweating, nausea, vomiting, bradycardia, hypotension, syncope
Anxiety, EPS/akathisia
EPS/akathisia, psychosis
Anorexia
M1 (central)
M2-4 (peripheral)
5-HT1A
5-HT2A
5-HT2C
To prevent or at least reduce the intensity of withdrawal and rebound symptoms
during the transition to antipsychotic treatment, several strategies are available. These
include the use of benzodiazepines, antihistamines, anticonvulsants, anticholinergics, beta
blockers or the prolongation of the switching phase and the application of the targeted
switching strategy based on the specificities of the molecules involved in the switch [57].
Unfortunately, even in the case of switching strategies, the literature is scarce and usually
about schizophrenia or schizoaffective disorders [58], while dementia is under-represented,
especially regarding recent literature. A systematic review and meta-analysis evaluated the
available literature regarding immediate versus gradual antipsychotic switch in patients
with schizophrenia [59]. In this meta-analysis, no difference was found in terms of several
clinical outcomes between the two groups (immediate vs. gradual discontinuation when
switching drug). That finding is partially at odds with the previous literature, suggesting
gradual discontinuation in order to mitigate rebound effect; however, the lack of difference
could be due to the different pharmacological properties other than towards dopamine
receptors, as well as to the dose equivalents of the new drugs [59]. A review published
by Cerovecki et al. evaluated the antipsychotic switching, but again on a population with
schizoaffective disorders [54]. In this review, few examples of drug switching have been
reported, with relevant diverse events. However, the switches reported should be read
with a critical approach by the clinician treating BPSD in dementia, since the populations
examined are hugely different, some of the studies were sponsored, and few of the reported
papers were case reports of purely psychiatric subjects [54]. The finding from the broad
literature review, which could certainly be useful, was that exacerbation of psychosis
was more frequent when switching from clozapine or olanzapine to other SGA; rebound
psychosis was more evident when switching from the same above mentioned drug to
risperidone or aripiprazole [54]. This definitely supports the slow cross-tapering switch,
possibly with the support of benzodiazepine or anticholinergic compounds [54].
aripiprazole [54]. This definitely supports the slow cross-tapering switch, possibly with
the support of benzodiazepine or anticholinergic compounds [54].
The setting of a specific switching strategy between antipsychotics can greatly contribute
in reducing the risk of the phenomenon described above [54,57]. “Abrupt
Pharmaceuticals 2021, 14,
246
9 ofswitch”
13
is the simplest strategy in which one drug is immediately replaced with another, with a
full and immediate discontinuation of the first antipsychotic drug and subsequent full
dose introduction
of theofsecond
one.
This type
of switching
often occurs
clinical
The setting
a specific
switching
strategy
between antipsychotics
canin
greatly
con-practribute inabruptly
reducing the
riskautonomously
of the phenomenon
described above
[54,57]. “Abrupt
switch” and
tice, as patients
and
discontinue
antipsychotic
treatment
is
the
simplest
strategy
in
which
one
drug
is
immediately
replaced
with
another,
with
full
then the physician is forced to revert to adequate antipsychotic treatment just asa quickly,
and immediate discontinuation of the first antipsychotic drug and subsequent full dose
when he notices the interruption. If, instead, it is planned by the physician, it should be
introduction of the second one. This type of switching often occurs in clinical practice,
reserved exclusively
for cases
in which adiscontinue
patient reports
a serious
adverse
event
as patients abruptly
and autonomously
antipsychotic
treatment
and then
the attributablephysician
to ongoing
antipsychotic
therapy,
since this
strategy
is quickly,
associated
with a
is forced
to revert to adequate
antipsychotic
treatment
just as
when he
notices
the interruption.
If, instead,
is planned
by the physician,
be reserved
greater risk
of rebound
phenomena
[55].it “Taper
switch”
consists itofshould
the gradual
suspencases in which a patient reports a serious adverse event attributable to
sion of theexclusively
first drugforwith
the immediate start of the second antipsychotic at therapeutic
ongoing antipsychotic therapy, since this strategy is associated with a greater risk of redosage; this
modality
can [55].
be used
inswitch”
cases where
new
drugsuspension
does notofrequire
bound
phenomena
“Taper
consists the
of the
gradual
the first titration. “Cross-taper
consists
suspensionatoftherapeutic
the first drug
associated
drug withswitch”
the immediate
startofofthe
thegradual
second antipsychotic
dosage;
this
can be used
in casesin
where
new drugofdoes
not new
requireantipsychotic.
titration. “Cross-taper
with the modality
progressive
increase
thethedosage
the
“Plateau
switch”
consists
of
the
gradual
suspension
of
the
first
drug
associated
with
the
progressive
cross-taper switch” consists of the gradual initiation of the new antipsychotic until
increase in the dosage of the new antipsychotic. “Plateau cross-taper switch” consists of
reaching the
full dose, followed by a subsequent gradual withdrawal of the first drug.
the gradual initiation of the new antipsychotic until reaching the full dose, followed by a
The period
of
co-administration
of the
two
mustoftake
place for a of
period
of
subsequent
gradual withdrawal
of the
firstmolecules
drug. The period
co-administration
the
time that two
allows
the new
reach
the that
maximum
concentration
peak,
molecules
mustantipsychotic
take place for a to
period
of time
allows the
new antipsychotic
to and
reach
the
maximum
concentration
peak,
and
therefore
be
able,
when
the
suspension
of
therefore be able, when the suspension of the first molecule begins, to bind to the recepthe first molecule begins, to bind to the receptor systems [58]. Figure 1 shows the possible
tor systems
[58]. Figure 1 shows the possible drugs-switching schemes
drugs-switching schemes.
Figure 1. Potential drug-switching schemes. In each panel the old drug is blue, the new drug is red.
The x axis represents the timeline and the y axis the percentage of the target dose. The abrupt switch
consists of the immediate interruption of the old drug, starting the new drug at full dose. In the taper
switch, the old drug is gradually reduced while the new drug is started at full dose. Cross-taper
switch consists of gradual reduction of the old drug with gradual increase of the new drug, without
overlapping the full doses. Plateau cross-taper switch consists of gradual increase of the new drug,
a short overlapping of the two drugs at full dose and then gradual reduction of the old drug.
Pharmaceuticals 2021, 14, 246
Cross-taper switch consists of gradual reduction of the old drug with gradual increase of the new
drug, without overlapping the full doses. Plateau cross-taper switch consists of gradual increase
the new drug, a short overlapping of the two drugs at full dose and then gradual reduction of the
old drug.
10 of 13
Successful antipsychotic switches require planning, time, accurate dosing an
knowledge of the pharmacokinetic and pharmacodynamic characteristics of the an
Successful
antipsychotic
planning,
time,
accurate
psychotics
involved
in the switches
switch. require
Considering
the
burden
of dosing
BPSDand
for knowlpatients, car
edge of the pharmacokinetic and pharmacodynamic characteristics of the antipsychotics
givers and the healthcare systems, the choice of the best strategy for the drug switchin
involved in the switch. Considering the burden of BPSD for patients, caregivers and the
or healthcare
tapering,systems,
whenever
necessary,
represents
a the
crucial
in the
management
the choice
of the best
strategy for
drug step
switching
or tapering,
when- of a p
tient
with
dementia.
Strategies
requiring
a gradual
tapering
off of with
the first
antipsychot
ever
necessary,
represents
a crucial
step in the
management
of a patient
dementia.
with
a
progressive
increase
of
the
second
drug
would
probably
be
the
safest
Strategies requiring a gradual tapering off of the first antipsychotic with a progressive in a fra
increasewho
of themay
second
drug
would probably and
be thebe
safest
in a frail
patient, who
mayseveral
have drug
patient,
have
polypathology
already
prescribed
with
polypathology
and
be
already
prescribed
with
several
drugs.
Figure
2
shows
a
possible
flow
Figure 2 shows a possible flow chart when approaching a patient with BPSD,
such as a
chart when approaching a patient with BPSD, such as agitation, aggression, hallucination
itation, aggression, hallucination or delusions.
or delusions.
Figure 2. Flow chart for approaching patients with BPSD (in particular delusions/agitation/aggression/psychosis, hallucinations).
Pharmaceuticals 2021, 14, 246
11 of 13
5. Conclusions
In recent years, conventional antipsychotics, such as haloperidol, have been replaced
by atypical antipsychotics for the treatment of psychosis in dementia. However, they have
minimal efficacy on psychotic symptoms and are associated with several adverse effects,
such as increased risk of falls and stroke. Nevertheless, the major concern is their association with an increased risk of death. Regulatory agencies warn that these medications
should be avoided in older adults with dementia, while practice guidelines from specialist
societies recommend that they should be reserved as a second-line treatment for behavioral symptoms, when these patients are unresponsive to non-pharmacological strategies.
Among atypical antipsychotics, the use of risperidone, olanzapine and aripiprazole appears
to be supported by stronger data when compared with quetiapine for treating BPSD. Even
though these medications have reached a nearly acceptable trade-off between effectiveness
and safety, a single most effective and safe treatment is yet to be found. The management
of psychiatric symptoms in dementia represents an important challenge for clinicians, who
have to tailor the therapy according to the patients’ symptoms, comorbidity and polytherapy, bearing in mind the high risk of adverse events; it is recommended to use the lowest
dose possible and to attempt therapy discontinuation whenever possible. A standardized
treatment algorithm would be desirable, especially considering the prevalence of such a
devastating disease.
Author Contributions: Conceptualization, V.C. and G.D.F.; methodology, V.C. and G.D.F.; resources,
data curation, original draft preparation, S.R., R.F. and S.E.; writing—review and editing, V.C., G.D.F.,
C.O., G.R. and F.M.; supervision, F.M. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Data Availability Statement: Data sharing not applicable.
Conflicts of Interest: The authors have no conflict of interest to declare.
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