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Tardive Dyskinesia: A Clinical Primer
TARDIVE DYSKINESIA: WHY AGE MATTERS
A look at the onset and mechanisms behind these involuntary movements. Plus,
special considerations for prescribing dopamine receptor blocking agents to
older adults.
Mar 15, 2024
4 Min Read
Chintan Shah, MD, Movement disorders fellow
Diagnostic criteria for tardive dyskinesia, or TD, are involuntary movements
that persist for at least 1 month after discontinuation of dopamine receptor
blocking agents (DRBAs).1 It has been difficult to identify who is at risk of
developing TD, however, only 25% of patients on DRBA treatment develop the
condition.2 Herein, we look at risk factors, especially among older adults, and
the mechanisms behind varied times of TD onset.
GENERAL TARDIVE DYSKINESIA RISK FACTORS
Tardive dyskinesia involves repetitive stereotyped movements that occur after
long-term use of DRBA medications, which are indicated for the treatment of
bipolar disorder, schizophrenia, psychosis, and affective disorders.
Risk factors for developing TD include age above 60 years, female sex, African
or Caucasian ancestry, and history of underlying mood or substance use
disorders.3 Other factors that play a role in the development of TD include the
type of DRBA (first-generation antipsychotics vs second-generation
antipsychotics), dosage, duration of treatment, and the intermittent nature of
treatment. Various genetic factors have also been implicated in the development
of TD, although the evidence is limited.
The risk of delayed onset of TD increases with advanced age, prolonged treatment
with DRBA, abrupt cessation, medication noncompliance, and frequent alterations
of dosage.
NO CLEAR PATTERN FOR TD ONSET
Despite known risk factors, TD can be unpredictable in terms of onset. There
have been case reports of the condition occurring as early as 2 to 3 weeks after
exposure to DRBA.4 In most cases, TD occurs after prolonged treatment with DRBA,
with highest risk of symptom development occurring 2 to 3 years after treatment
with DRBAs, especially in those over 60 years of age.5,6
With advanced age, there is also an increased risk of developing TD several
months after discontinuation of the offending drug. There have been case reports
of TD onset 8 to 10 months after stopping antipsychotic treatment.7
WHY TD ONSET VARIES
The variable onset of TD is likely due to its underlying pathophysiology, which
is not fully understood. Several mechanisms have been postulated but a
combination of multiple mechanisms is likely at play. Chronic blockade of
dopamine receptors with DRBAs used to treat psychiatric disorders can lead to
upregulation of those dopamine receptors with associated hypersensitivity.3 The
increased activity and sensitivity of these dopamine receptors result in
hyperkinetic movements noted in TD.
The duration of dopamine receptor blockade and the affinity of DRBA to the
dopamine receptor (dictated by the type of DRBA and its dosage) may explain the
difference between the variable risk of TD development associated with different
antipsychotic treatments (FGAs vs. SGAs, for example). FGAs bind more tightly to
dopamine receptors (85% occupancy) than SGAs (35% to 75% occupancy), correlating
with its significantly higher risk of TD.3 However, this mechanism does not
explain the development of TD that occurs after discontinuation of DRBA, which
should theoretically reduce the risk of TD by minimizing dopamine receptor
hypersensitivity via reduction in overall dopamine receptor blockade with
cessation of treatment.
For those individuals with delayed onset of TD or onset of TD after
discontinuation of DRBA, another mechanism is likely more explanatory. There is
evidence that chronic DRBA use can lead to neuronal damage and degeneration via
increased oxidative stress from free radical formation. This process occurs
gradually and can take several months to years before clinical symptoms can be
observed.8
In addition, DRBAs over time are hypothesized to impair synaptic plasticity
between the basal ganglia and sensorimotor cortex, which are both involved in
regulation of movement.3 The neurodegenerative damage from oxidative stress and
impaired synaptic plasticity may explain the irreversible nature of TD in some
patients.
UNIQUE RISKS FOR OLDER PATIENTS
Advanced age (over 60 years) is the strongest risk factor for development of
TD.9 There is a 2- to 5-fold increase in incidence rate of TD annually in older
adults when compared to younger adults (under 45 years). The incidence of TD in
those over age 60 was 5.9% at 3 months after DRBA use, 26.1% at 12 months, 51.7%
at 2 years, and 59.8% at 3 years.10 It is unclear why the risk of TD increases
with age but some research has linked it to age-related neurological changes and
slowdown in overall metabolism.9 The increased incidence of TD in older adults
is irrespective of FGA vs SGA use, although the overall risk appears to be much
less with SGAs.
ANTIPSYCHOTIC PRESCRIBING IN OLDER ADULTS
As a result, caution should be exercised when considering treatment with DRBAs
in older adults. Older patients with coexisting cognitive impairment, prior
neurological insult, long duration of psychiatric illness, and history of
substance use disorder are more likely to develop TD.
If DRBA treatment is absolutely warranted, preference for SGAs should supersede
the use of FGAs. DRBAs such as clozapine, quetiapine, and aripiprazole are
associated with reduced dopamine receptor blockade compared to other DRBAs
although the risk of TD is not eliminated with these agents. The lowest
effective dose should be identified with gradual titration if necessary.
MONITORING
Follow-up visits at least every 6 months should also focus on evaluation of TD
symptoms because early detection and treatment can significantly improve quality
of life and possibly result in favorable long-term prognosis.11 It is also
essential to monitor for medication adherence as intermittent use and abrupt
discontinuation of DRBAs increase the likelihood of TD.
In the event DRBA treatment needs to be discontinued due to TD, gradual tapering
off the medication is recommended as opposed to abrupt discontinuation,
regardless of the dosage. DRBA medication changes should occur under the
supervision of a psychiatrist and/or neurologist.
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do not Block Dopamine Receptors: Rare or Non-existent: Literature Review.
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TARDIVE DYSKINESIA: A CLINICAL PRIMER
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review treatment strategies for their management based on the current guidelines
and evidence in the literature.
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