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Tardive Dyskinesia in Older Persons Taking

Antipsychotics

Leslie Citrome, Stuart H Isaacson, Danielle Larson & Daniel Kremens

To cite this article: Leslie Citrome, Stuart H Isaacson, Danielle Larson & Daniel Kremens (2021)
Tardive Dyskinesia in Older Persons Taking Antipsychotics, Neuropsychiatric Disease and
Treatment, , 3127-3134, DOI: 10.2147/NDT.S328301

To link to this article: https://doi.org/10.2147/NDT.S328301

© 2021 Citrome et al.

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Tardive Dyskinesia in Older Persons Taking

Antipsychotics

Leslie Citrome 1 Abstract: Tardive dyskinesia (TD) is a hyperkinetic movement disorder caused by the use
Stuart H Isaacson 2 of dopamine receptor-blocking agents (DRBAs), a category of medications that includes
Danielle Larson 3 first- and second-generation antipsychotics (APs) and agents such as metoclopramide that are
Daniel Kremens 4 used for the treatment of nausea and gastrointestinal dysmotility. While TD can affect people
of all ages, older age is associated with increased risk of TD and also with the emergence of
1
New York Medical College, Valhalla, NY,
TD occurring after shorter treatment durations and lower dosages of DRBAs. TD is char­
USA; 2Parkinson’s Disease and Movement
Disorders Center of Boca Raton, Boca acterized by involuntary movements that include the face, limbs, and trunk, and is associated
Raton, FL, USA; 3Parkinson’s Disease and with increased comorbidities, social stigmatization, and impaired physical and mental health.
Movement Disorders Center,
Northwestern University Feinberg Once present, TD tends to persist despite AP dose adjustment or discontinuation. Even with
School of Medicine, Chicago, IL, USA; the use of US Food and Drug Administration (FDA)-approved medications for TD, symp­
4
Department of Neurology, Jefferson toms may persist. Because the leading hypothesis for the pathophysiology of TD has been
Comprehensive Parkinson’s Disease and
Movement Disorders Center, Thomas dysregulation of dopamine transmission due to treatment with DRBAs, APs that avoid
Jefferson University, Philadelphia, postsynaptic dopamine receptor blockade may provide an alternative therapeutic approach
PA, USA
for patients who require an AP. In this review, we discuss the risks, burdens, prevention, and
management of TD, with a focus on older people.
Keywords: tardive dyskinesia, antipsychotic medications, age

Introduction
Tardive dyskinesia (TD) is a hyperkinetic movement disorder caused by dopamine
receptor-blocking agents (DRBAs), a category of medications that includes anti­
psychotics (APs) and some agents used to treat nausea and gastrointestinal dysmo­
tility, such as metoclopramide.1 The Diagnostic and Statistical Manual of Mental
Disorders, 5th edition, defines TD as involuntary athetoid or choreiform move­
ments. Symptoms must last for at least a few weeks and develop in association with
the use of a neuroleptic medication for at least a few months.2 TD is often
irreversible, can impact daily life, and can be socially stigmatizing.3 While all
individuals treated with DRBAs are at risk for developing TD, older individuals
are at higher risk and particularly vulnerable to developing this disorder, even after
shorter exposure to newer second-generation APs.4–7
In addition to their US Food and Drug Administration (FDA)-approved indica­
tions, APs have also been used for non-approved (ie, “off-label”) indications,7
including neuropsychiatric symptoms associated with Parkinson’s disease or
dementia. The increasing and widespread use of APs has led to more elderly people
Correspondence: Leslie Citrome
New York Medical College, 40 Sunshine being placed at risk of TD.8–11 Moreover, older individuals on APs may face
Cottage Road, Valhalla, NY, 10595, USA a greater risk for complications related to TD, as they are more prone to falls,
Tel +1 845 362-2081
Email [email protected] orthostatic hypotension, somnolence, and generally have a greater burden of

Neuropsychiatric Disease and Treatment 2021:17 3127–3134 3127

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 Citrome et al Dovepress

comorbidities than younger people.12–16 The aim of this study initiated prior to the widespread use of second-
review is to examine the risk, burden, and management of generation APs calculated a yearly cumulative incidence
TD with a particular focus on the elderly. of TD of 4%–5%.27 The frequent occurrence of TD and
acute extrapyramidal symptoms, such as drug-induced
Overview of Tardive Dyskinesia parkinsonism and acute dystonia, encouraged the develop­
TD is characterized by a delayed onset of involuntary motor ment of second-generation APs, which were intended to
movements in the face, trunk, and limbs after exposure to minimize the incidence of adverse neurological effects.
DRBAs.4,17 Involuntary movement are classically peri-oral, Although acute drug-induced parkinsonism and acute dys­
including grimacing, tongue protrusion, and lip puckering, tonia are lessened, TD has not been eliminated. The annual
but also include neck, shoulder, and limb movements.18 In prevalence of TD among patients receiving APs was esti­
some cases, symptoms can be severe enough to interfere mated to be 7.6 to 9.7 per 1000 people according to a large
with breathing, speaking, eating, and ambulation.19,20 retrospective observational study of electronic health
TD is often irreversible and can impose long-lasting bur­ records, with nearly 80% of study participants
dens on psychosocial, physical, and economic health.4,21–23 using second-generation APs.15 A direct comparison of
Historically, assumptions that those afflicted are unaware of annualized incidence between first- and second-
their symptoms or unconcerned with them have obscured generation APs indicates a reduced but not eliminated
these burdens, especially among persons with schizophrenia risk of TD with use of second-generation APs (range of
who can have limited insight into their physical and mental 0.8% to 3% with use of second-generation APs vs 5.4% to
health.24,25 However, a recent study of those with a history of 7.7% with use of first-generation APs).6,29
AP use for the treatment of schizophrenia, schizoaffective The most important risk factors for the development of
disorder, mood disorder, and other psychiatric disorders, TD include older age and cumulative exposure to the
found that nearly 80% of subjects with a clinician-confirmed DRBA. Other risk factors include the dopamine-receptor
diagnosis of possible TD reported noticing recent involuntary binding affinity of the DRBA in question, female sex,
movements.21 Many of these individuals also felt that the mood disorders, dementia, and prior drug-induced
uncontrollable movements impacted their ability to engage parkinsonism.4,30–33 Smoking and substance abuse may
in daily activities, talk, or socialize.21 also be associated with a higher risk of developing TD.33
The degree to which those with TD experience reduced
general health, life enjoyment and satisfaction, and TD in Older Populations
enhanced social withdrawal is generally proportional to As noted, age is a key risk factor for developing TD.31,34
the severity of the symptoms.3 The disorder can impact A study of 404 people aged ≥55 years reported cumulative
leisure activities or the willingness to participate in com­ TD incidences of 26%, 30%, and 60% after the first, second,
munity activities. TD can also hinder the ability to find and and third year, respectively, of first-generation AP use.35 This
maintain employment due to the symptoms themselves or is considerably higher than that observed in younger people;
embarrassment caused by the symptoms.21,26 The financial a meta-analysis of 32 randomized studies that included
impact of TD on the healthcare system can be consider­ 10,706 subjects of mixed ages calculated an annualized TD
able, as reported in a large, retrospective analysis that incidence of 6.5% with the use of first-generation APs.28
found that people with both TD and schizophrenia, mood Second-generation APs offer older people a reduced risk of
disorders, or other psychiatric disorders experience 29% approximately 6% and 7% after the first year of use to 11%
more hospital admissions, 5% more outpatient visits, and after the second year of use in those who are naïve to first-
21% more emergency room visits than those without generation APs. However, the risk (nonetheless remains
TD.22 This results in a nearly doubling of the healthcare- higher than the incidence of ≤3% observed among younger
related financial burden for individuals with TD from adults treated with second-generation APs.29,36 Although TD
$28,777 to $54,656 over a 2-year period.22 risk increases in a dose-dependent manner, older patients are
susceptible after exposure to even low doses of second-
Prevalence and Risk of TD generation APs.4,37 A study of 255 older patients with
The mean prevalence of TD in people treated with APs dementia (mean age: 82.5 years) found that 1.7% of patients
was 20–25% according to meta-analyses of articles pub­ treated daily with 0.75 to 1.5 mg risperidone for 1 year
lished between 1959 and 2015.27,28 A 20-year longitudinal developed TD; in contrast, no new cases of TD were reported

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in a mixed-age adult population of 541 patients treated with people.3,16 Older individuals are also uniquely vulnerable
a mean dose of risperidone 3.9 mg/day for 6 months.37,38 to the physical consequences of TD, such as impaired gait
Similarly, no change from baseline was observed in TD and balance, which can lead to falls.16,26 TD in older
symptoms among adults aged ≤65 years after 1 year of 4 to patients often presents as oro-bucco-lingual dyskinesia,
10 mg risperidone daily.39 The mechanism underlying age- and these movements can interfere with eating and swal­
related increased susceptibility is unclear but may be due to lowing; incidents of choking resulting from respiratory TD
higher cumulative exposure to APs as well as an age-related have been reported.7,19,46 Further, oro-bucco-lingual TD
decrease in dopaminergic neurons in the substantia nigra.40 can cause loosening of natural and artificial teeth and be
Because APs are sometimes used off-label for demen­ augmented by edentulousness and denture use; edentulous­
tia-related psychosis and aggression,8,11 TD can be ness itself can cause abnormal movements of the mouth in
encountered in this population, particularly within facil­ the absence of neurological disorders such as TD.26,46,47
ities that care for older people. Up to 33% of patients Older patients may also be affected by dyskinesias of the
residing in nursing homes or assisted living facilities limbs, trunk, and respiratory system, with symptoms such
receive APs, predominantly for off-label indications.8 as grunting.7,26,48
A survey of 350,000 nursing home residents in 8 states, The observation that older people with TD are also at
representing 40% of residents nationally, found that in increased risk of cardiac, metabolic, and other movement
2006, 27.6% of residents had taken APs in the last 7 disorder comorbidities complicates treatment of TD in
days, and only 20.7% of these were for treatment of the these patients.12–15 Lastly, the high healthcare utilization
primary indications of schizophrenia or bipolar disorder.41 costs associated with TD are likely to severely tax the
The National Nursing Home Survey of 300,000 residents resources of older people on fixed or limited incomes
found that 23% of respondents had received at least and stress the healthcare system in general.22 Given these
1 second-generation AP, and 86.3% of these prescriptions considerable impacts, treatment plans for older individuals
were for off-label indications.42 Dementia is one of the with psychiatric conditions should include modification of
most common indications for off-label AP use in these prescribing practices to minimize the risk of TD.
facilities, despite the bolded “black box” warning against
AP use in patients with dementia-related psychosis.8,11 Mechanisms of TD with APs
Behavioral issues related to dementia may in part drive Understanding the pathophysiology of TD is essential to
AP use in this population. Crystal et al found that half of choosing therapies for psychiatric conditions that mini­
residents with dementia and aggressive behavior received mize the risk of this disorder in older patients. While
AP treatment, while 40% and 23% of patients with non­ there is not a universally accepted mechanism through
aggressive dementia or dementia without behavioral symp­ which APs drive the development of TD, a leading
toms, respectively, also received APs.41 Other common hypothesis revolves around the dysregulation of dopami­
reasons for off-label AP use among older people are anxi­ nergic transmission.49,50 Antagonism of postsynaptic
ety and insomnia.8 The prevalence of off-label AP use, dopamine D2 receptors in the mesolimbic pathway, speci­
particularly among older individuals, has prompted the fically in the ventral striatum, drives efficacy of APs in
Centers for Medicare and Medicaid Services to issue reducing positive symptoms associated with psychosis.
guidelines and fact sheets recommending against this However, long-term blockade of D2 receptors in the
practice,43 and long-term care settings are compelled to nigrostriatal pathway, specifically in the dorsal striatum,
adhere to efforts to mitigate their use. However, recent can lead to an increase in the number and function of
studies suggest AP use outside of approved indications postsynaptic dopamine D2 receptors (often referred to as
continues.44,45 the “supersensitivity” or “hypersensitivity” hypothesis)
subsequently interfering with voluntary motor
Impact of TD in Older People control. 4,51,52
This enhanced sensitivity to dopamine in
The impact of TD on an individual’s physical, mental, and the dorsal striatum can lead to several types of motor
economic health may intensify with age.3,22 The social and symptoms, including TD. Genetic studies in support of
emotional effects of symptoms are highly debilitating for a role for dopamine hypersensitivity in TD include obser­
people with TD of all ages, but feelings of isolation and vations that mutations in the PIP5K2A and DRD2 dopa­
depression may be especially profound for older mine receptor genes and in the glycine variant of the

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dopamine D3 receptor have been linked to the develop­ across 3 studies, whereas across 5 studies, the risk estimates
ment of TD in people with schizophrenia.53–55 associated with olanzapine, risperidone, quetiapine, or amisul­
Second-generation APs are thought to carry a lower risk pride ranged from 0.5% to 1.5%. In addition, because older
for the development of TD compared with first-generation people both experience benefit from second-generation APs at
APs because although both types of APs are low doses and are at greater risk of developing TD after
DRBAs, second-generation APs are also antagonists at pre­ minimal exposure, treatment regimens should reflect these
synaptic serotonin 5-HT2A receptors, which can lessen the sensitivities and implement the lowest effective AP dose.7,62
risk of drug-induced movement disorders in general. In addi­ Several nondopaminergic approaches to treat psychosis
tion, some second-generation APs have a lower binding are also in development. Serotonin receptor inhibition has
affinity to the postsynaptic dopamine receptor as well.18,56,57 not been associated with TD, and selective inverse agon­
Investigational uses of functional magnetic resonance ism/antagonism of 5HT receptors may be a therapeutic
imaging (fMRI) to help elucidate the pathophysiology of strategy that would mitigate the risk of TD.63 Another
TD are also of interest. For example, two recent reports potential preventative strategy is treatment of psychiatric
demonstrated statistically significant differences in gray mat­ disorders through selective agonism of the trace amine-
ter volume and resting state functional connectivity of motor- associated receptor 1 (TAAR1), an approach that has
related brain regions of interest in patients with schizophrenia recently been shown to improve symptoms of schizophre­
treated with antipsychotics with and without a TD diagnosis. nia in adults and does not induce motor abnormalities in
Gray matter volumes of the brainstem, inferior frontal and animal models.64 Targeting the muscarinic system with
precentral gyri, cuneus, and lingual gyrus were significantly a combination of xanomeline and trospium has also been
different in patients with TD than in those without.58 proposed as a nondopaminergic strategy for mitigating TD
Similarly, patients with TD exhibited a reduction in resting risk.65,66
state functional connectivity between the right postcentral
gyrus and the inferior frontal gyrus of the left triangular
part compared with patients without TD.59 Gray matter
Current Therapeutic Strategies for TD in
volumes of the cuneus and lingual gyrus and the reduction Older Patients
in resting state functional connectivity observed were also The first step in developing the optimal treatment strategy
correlated with TD severity, as assessed by the total score on for TD is timely diagnosis, which requires the clinician to
the Abnormal Involuntary Movement Scale, providing be routinely vigilant.67 Diagnosis is based on history of
further support that changes in gray matter volume or func­ exposure to DRBAs, and a minimum duration of only 1
tional connectivity may be related to the pathophysiology of month of AP exposure is required to diagnose TD in
TD.58,59 The use of fMRI in evaluating TD remains investi­ individuals aged ≥60 years, compared with 3 months in
gational, and its relevance in older populations deserves younger adults.2,7,60
further study. An early strategy to mitigate TD symptoms involves
modification of the existing AP medication regimen if
Strategies for Minimizing TD Risk clinically feasible.68 However, success with this
TD can be irreversible, highlighting the need for preventative approach is often limited.23,68,69 Two vesicular monoa­
strategies. Many clinicians focus primarily on limiting the use mine transporter 2 (VMAT2) inhibitors, valbenazine and
of TD-inducing medications and secondarily on detecting TD deutetrabenazine, have been approved by the US FDA
symptoms early.51,60,61 Considering the pharmacology of indi­ to treat TD.68,70,71 Recent guidelines for the treatment of
vidual APs with an understanding of proposed TD pathophy­ schizophrenia recommend VMAT2 inhibitors as first-
siology informs the selection of therapies that are least likely to line therapy for patients who have moderate to severe
induce TD. Use of less potent dopamine receptor or disabling TD or for patients with mild TD on the
blocking second-generation APs instead of first-generation basis of such factors as patient preference, associated
APs may reduce TD risk. Correll and colleagues presented impairment, or effect on psychosocial functioning.72 In
the initial support for a lower risk of TD associated two recent studies of subjects aged ≥55 years who had
with second-generation APs compared with first-generation participated in clinical trials conducted by the manufac­
APs in a meta-analysis of 11 randomized studies.6 Here, the turer, Sajatovic et al demonstrated that valbenazine
annual TD risk estimate associated with haloperidol was 5.4% (median: 61 years, range: 55–84 years) and

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 Dovepress Citrome et al

deutetrabenazine (mean age: 63.1 years, range: 55–81 receptors in the dorsal striatum, and thus do not carry
years are well tolerated in older individuals.73,74 Of a significant risk for TD, are needed.
note, VMAT2 inhibition manages the symptoms of TD
but does not cure them; dyskinetic movements generally Abbreviations
return when the VMAT2 inhibitor is discontinued.75 APs, antipsychotics; DRBAs, dopamine receptor-blocking
Although anticholinergic agents may effectively treat agents; FDA, Food and Drug Administration; TD, tardive
acute drug-induced parkinsonism, these medications can dyskinesia; VMAT2, vesicular monoamine transporter 2.
worsen TD.23 Anticholinergic drug burden is also associated
with impaired cognition. Discontinuation of anticholinergic Acknowledgments
medication leads to an improvement of TD symptoms in Medical writing support for the development of this manu­
approximately 60% of people, and if enacted, should be script, under the direction of the authors, was provided by
done gradually.23,76 An additional benefit from deprescribing Sarah Marshall, PhD, of Ashfield MedComms, an Ashfield
anticholinergic medication would be a lessening of the mem­ Health company, and Dena McWain (Ashfield
ory impairment and other anticholinergic adverse effects MedComms) copyedited and styled the manuscript per
associated with this class of drug.77 journal requirements.
Avoiding TD by eliminating exposure to DRBAs may
be the best option for older persons. Several novel agents Author Contributions
are being studied for their antipsychotic properties. All authors made a significant contribution to the work
Alternative mechanisms, including serotonin inverse agon­ reported, whether that is in the conception, study design,
ism/antagonism in the absence of dopamine receptor execution, acquisition of data, analysis and interpretation,
blockade, agonism of TAAR1 receptors, and modulation or in all these areas; took part in drafting, revising or
of muscarinic cholinergic receptors, may provide different critically reviewing the article; gave final approval of the
therapeutic approaches for patients who require version to be published; have agreed on the journal to
a medication with an AP effect and avoid contributing to which the article has been submitted; and agree to be
the risk of developing TD.63–66 accountable for all aspects of the work.

Funding
Conclusion Acadia Pharmaceuticals Inc., San Diego, CA, provided
TD is a particular concern for elderly individuals treated funding for medical writing and editorial support in the
with DRBAs, including second-generation APs. The pre­ development of this manuscript.
valence of TD in this population is up to 5 to 6 times that
of younger people and is encountered clinically in part Disclosure
because of the off-label prescription of APs for dementia- Leslie Citrome: In the past 12 months, consultant: AbbVie,
related behavioral and psychological disorders.7,11 In addi­ Acadia, Alkermes, Allergan, Angelini, Astellas, Avanir,
tion to the TD symptoms themselves, older people may be Axsome, BioXcel, Boehringer Ingelheim, Cadent
more severely impacted by associated comorbidities and Therapeutics, Eisai, Impel, Intra-Cellular Therapies, Janssen,
impaired physical and mental health.13–15,78 Karuna, Lundbeck, Lyndra, Medavante-ProPhase, Merck,
Although the recent approval of VMAT2 inhibitors pro­ Neurocrine, Noven, Otsuka, Ovid, Relmada, Sage,
vides a new therapeutic option once TD occurs, avoiding this Sunovion, Teva, University of Arizona, and one-off ad hoc
often irreversible movement disorder would be preferred. An consulting for individuals/entities conducting marketing, com­
important strategy for mitigating TD risk is prescribing APs mercial, or scientific scoping research; Speaker: AbbVie,
that address psychiatric conditions while minimizing the risk Acadia, Alkermes, Allergan, Angelini, Eisai, Intra-Cellular
of developing this disorder. Currently, second-generation Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka,
APs are recommended over first-generation APs.23 Sunovion, Takeda, Teva, and CME activities organized by
However, the risk of TD among older individuals persists at medical education companies such as Medscape, NACCME,
a rate of approximately 6% with use of second-generation NEI, Vindico, and universities and professional organizations/
APs.36 Newer APs that are effective in treating mental health societies; Stocks (small number of shares of common stock):
disorders but that do not block postsynaptic dopamine D2 Bristol-Myers Squibb, Eli Lilly, J & J, Merck, Pfizer

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