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Clinical Management of
Tardive Dyskinesia (TD)

Dopamine receptor hypersensitivity and tardive dyskinesia development

TD is a complex involuntary movement disorder that has a variety of phenomenologically distinct clinical manifestations. It is thought that dopamine receptor hypersensitivity is a cause of this disorder. According to this theory, chronic dopamine antagonism results in gradual hypersensitization of dopamine receptors, which initiates a pathogenic cascade leading to excess dopamine signaling.1-3

TD remains a significant burden among certain patient populations, such as those receiving treatment with Dopamine Receptor-Blocking Agents (DRBAs). DRBAs are primarily utilized as antipsychotic drugs (APDs) for treating a range of psychiatric disorders.1-4

Effective TD management involves monitoring for early signs and prompt intervention, as well as routine clinical assessment. Due to the heterogeneity of patients and other clinical challenges, it is important to consider a patient-centric approach for managing TD.1,2,5-8

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Understanding the complexity of tardive dyskinesia presentation and management

Optimal management of TD requires a full appreciation of the complexity associated with this disease.6-8

Seven facets of clinical complexity

1. Patient Types

Broad patient demographics
Regardless of age, race, gender, or other characteristics, anyone who has taken DRBAs can develop TD. DRBAs are used for an assortment of therapeutic purposes, including as1,9

  • APDs

  • Tricyclic antidepressants (eg, amoxapine)

  • Antiemetics and other medications for gastrointestinal disorders (eg, metoclopramide, promethazine)

As a result of the versatile use of DRBAs, it is difficult to define TD patient types with a fixed set of demographics.1,9

There are certain demographic and medical risk factors associated with TD1-3,9-11

  • Older age (particularly 55 years or older)1-3,9-11

  • Female gender (especially those who have gone through menopause)1-3,9,11

  • Non-Caucasian ethnicity1,3,11

  • History or presence of brain damage, dementia, acute extrapyramidal symptoms, major affective disorder, alcohol or other substance abuse, diabetes mellitus, or HIV/AIDS1-3,9,11

  • Longer exposure to and higher doses of DRBAs1-3,9-11

    • TD symptoms tend to appear ≥3 months from DRBA exposure (≥1 month for elderly)1-3,11

      • TD can also develop within 4 weeks of DRBA withdrawal (8 weeks for a depot DRBA)

    • Higher doses are associated with more risk2,9,11

Variability in patient functionality and independence
An aspect of the heterogeneity of TD patients is the variable nature of their functionality and independence as it relates to their underlying psychiatric disorders. Clinical decisions in managing TD tmust be weighed against the impact on the patient’s psychiatric stability and overall level of daily functioning.1,2,5,8,10,12-15

Lack of patient awareness and symptom reporting
Patients are often not aware of their tardive dyskinesia and this may be a particular issue when presentation is in unexpected areas of the body.9,16

  • Lack of awareness may prevent patients from initiating a dialogue about their symptoms
The Abnormal Involuntary Movement Scale (AIMS) can be utilized to assess for signs of TD and measure severity of symptoms.5,11,17

2. Underlying conditions

Multifaceted underlying conditions

TD is most often managed in the presence of one or more underlying conditions.1,9-11

Underlying conditions associated with TD1,9-11

  • Psychiatric disorders
    • Schizophrenia
    • Bipolar disorder
    • Major depressive disorder
  • Gastrointestinal disorders

Clinicians must navigate a complex set of variables to find the optimal therapeutic regimen for patients with respect to their underlying conditions. For patients with psychiatric disorders, TD may prompt changes to the therapeutic regimen, compromising the stability of their underlying conditions.1,2,8,10,12-15

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3. Background therapies

Range of concomitant medications
A variety of concomitant medications may be in use among TD patients, including1,9-11

  • APDs (typical and atypical)

  • Antidepressants

Medication changes prompted by TD may destabilize patient’s overall symptom control that has been established with the concomitant medications.1,2,10,12-15
An image describing the location of involuntary movements in tardive dyskinesia: tongue, lips, jaw, trunk, extremities

4. Presentation

Location of involuntary movements1,5,9:

  • Tongue

  • Lips

  • Jaw

  • Trunk

  • Extremities

The spectrum of TD includes abnormal involuntary movements across various parts of the body.1,5,9

5. Severity

Differing degrees of severity

  • TD severity ranges from mild involuntary movements, which are often unnoticed by the patient, to a disabling condition1

  • TD usually evolves into a full syndrome over days or weeks, followed by stabilization of the symptoms, and a chronic but waxing and waning course1

  • Symptoms of TD fluctuate over time1,5

    • Symptoms can increase with emotional arousal, activation, or distraction, and diminish with relaxation, sleep, or volitional effort5

6. Impact

Multidimensional impact of TD
TD can potentially impact many aspects of personal wellness, including

  • Therapeutic: Jeopardizing psychiatric stability1,2,10,12-15

  • Functional: Diminishing everyday functioning5

  • Physical: Impairing physical health1,5

  • Psychosocial: Affecting emotional status10

TD may be associated with

  • Medication changes possibly undermining control of psychiatric condition1,2,10,12-15

  • Increased medical morbidity10

  • Poor quality of life10

  • Speech impairment5

  • Swallowing problems5

  • Pain and discomfort1

  • Dental issues18

  • Gait issues1

  • Breathing complications1,5

  • Emotional burdens10

TD can trigger a number of adverse outcomes across multiple areas, adding to the complexity of patient management.1,2,5,10,12-15

7. Diagnosis

Differential diagnosis of TD
Establishing a diagnosis of TD involves an examination of multiple factors, including DRBA exposure and characteristic clinical presentation. Excluding other reasonable possibilities is also a necessary part of differential diagnosis.1,2,5,13

TD diagnostic criteria1,2,5,13

DRBA Exposure

History of ≥3 months cumulative DRBA exposure (≥1 month in patients age 60 years or older)

or

Withdrawal from an oral DRBA within 4 weeks

or

Withdrawal from a depot DRBA within 8 weeks

Clinical point: TD often is masked by ongoing antipsychotic treatment and becomes apparent only when a drug is reduced, switched, or discontinued

Clinical presentation assessed on a scale (eg, the AIMS)

Presence of at least “moderate” abnormal involuntary movements in ≥1 body areas

or

Presence of at least “mild” movements in ≥2 body areas

Clinical point: DRBAs can cause a variety of phenomenologically distinct abnormal movements, which may frequently occur simultaneously in the same patient

Exclusion of conditions

Absence of other conditions that may produce abnormal involuntary movements

Differentiating between TD (inclusive of stereotypy) and drug-induced parkinsonism is a significant part of the diagnostic work-up1,5

Phenomenology Clinical Features

TD (stereotypy)

  • Nonrhythmic, repetitive, purposeless hyperkinetic symptoms usually of orofacial and lingual musculature: chewing; bruxism; protrusion, curling, or twisting of the tongue; lip smacking, puckering, sucking, and pursing; retraction, grimacing or bridling of the mouth; bulging of the cheeks; or eye blinking and blepharospasm

  • Choreoathetoid movements of the fingers, hands, or upper or lower extremities are common

  • Seemingly purposeful, repetitive and coordinated movements in the limbs or trunk may be observed, as well as axial symptoms affecting the neck, shoulders, spine, or pelvis

  • Respiratory muscles of the upper airways, chest, and diaphragm can be involved, causing gasping, stridor, interrupted flow of speech, paradoxical breathing, dyspnea on exertion, and other respiratory symptoms

  • Audible respiratory noises, and other noises, such as continuous humming or moaning, may be exhibited

Parkinsonism

  • Rest tremor, bradykinesia, rigidity

  • Drug-induced parkinsonism: If resolves within weeks of DRBA discontinuation

  • Tardive parkinsonism: If persists for months/years after DRBA discontinuation and normal DAT SPECT (abnormal DAT SPECT is indicative of underlying Parkinson's disease)

  • Clinical implication for TD: Dopamine agonists are often used to manage tardive parkinsonism but are not effective in TD

Given the complexity of TD, there is no one-size-fits-all approach to managing this multifactorial condition.

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There is an unmet therapeutic need in TD

Current standard of care is dose reduction or discontinuation of background therapies, which can potentially undermine the stability of underlying psychiatric conditions.1,2,8,10,12-15

There is an unmet need for therapeutic options that do not demand the disruption of concomitant medications and allow you to tailor treatment to each patient's needs.

Natural course of TD after drug discontinuation is unclear5
TD tends to persist for years or decades in the majority of patients, even after discontinuing the causative drug.1

  • In one study, only 12% of patients (n=42) achieved remission following discontinuation of DRBAs (for up to 6.7 years)1

  • In a separate study, investigators found that only 2% of patients (n=33) showed complete reversal of TD after drug discontinuation5,19

TD may even be precipitated by a dose reduction or sudden withdrawal of DRBAs.1

  • Studies have shown that withdrawal of APDs may lead to an initial worsening of TD in 33% to 53% of patients5

There is a need for a nuanced, patient-centric approach to manage clinical complexity5-8

Discontinuation of psychiatric medications may lead to deterioration of mental condition and exacerbation of psychiatric symptoms.5,10

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Prevalence of TD remains high

TD prevalence is estimated to be 20%-30% of patients treated with APDs.1,9,20

  • It varies among different age groups with prevalence increasing with advanced age1

TD remains highly prevalent with both typical and atypical APD treatments

  • A review of 41 studies (n=11,493) reported TD prevalence of20

    • 20.7% among patients treated with atypical APDs

    • 30.0% among patients treated with typical APDs

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Rate of new TD cases continues to be a concern

Annual incidence of TD is 5% among those treated with DRBAs, which increases with prolonged DRBA use.10

  • Risk of developing TD is 5 times greater after 5 years of DRBA exposure10

Higher risk of TD with advanced age
The incidence of TD is higher in middle-aged and elderly patients.1

  • 53% TD incidence after 3 years of DRBA use among psychiatric patients ≥55 years of age10

TD has not disappeared with the advent of atypical APDs
The use of atypical (second-generation) APDs was prioritized in an effort to substantially lower, if not eliminate, the development of TD; however, this has not been the case.2,21

Atypical APDs are also associated with the development of TD9

Annual incidence of drug-induced
movement disorder

A graph about the annual incidence of drug-induced movement disorder: 5.5% typical APDs. 3.9 atypical APDs.
Only a modest difference in the risk of developing drug-induced movement disorder was observed with typical versus atypical APDs, in a review of 12 studies (n=30,129).9
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There is a multidimensional impact on patients

TD can potentially impact many aspects of personal wellness, jeopardizing psychiatric stability, everyday functioning, and physical health.1,2,5,10,12-15

Therapeutic

The causative drug may be a critical component of the overall management plan and withdrawal may undermine control of psychiatric condition.1,2,10,12-15

  • TD is associated with increased medical morbidity10

  • Psychiatric patients experiencing drug-induced movement disorders have a worse prognosis and an increased risk of relapse leading to more frequent and prolonged hospitalizations22

TD may threaten the therapeutic alliance between a patient and the clinician.15

Functional

Drug-induced movement disorders are associated with a substantial reduction of quality of life. When severe, they can affect swallowing and speech and interfere with walking and other activities of daily living.5,10,22

Physical

Drug-induced movement disorders can have a detrimental impact on physical health. TD may be associated with breathing complications, abnormal gait, dental issues, and sensory phenomenon such as paresthesias and pain.1,5,18,22

Psychosocial

Drug-induced movement disorders can cause embarrassment, self-consciousness, and withdrawal from social connections. These effects may also diminish patients’ prospect of employment10,22

Successful management of each of these areas is essential for achieving and maintaining overall clinical stability.
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References:

  1. Waln O, Jankovic J. An update on tardive dyskinesia: From phenomenology to treatment. Tremor Other Hyperkinet Mov. 2013;3:tre-03-161-4138-1.
  2. Mehta SH, Morgan JC, Sethi KD. Drug-induced movement disorders. Neurol Clin. 2015;33(1):153-174.
  3. Jankelowitz SK. Treatment of neurolept-induced tardive dyskinesia. Neuropsychiatr Dis Treat. 2013;9:1371-1380.
  4. Chen JJ. Drug-induced movement disorders: A primer. US Pharm. 2007;32(11):HS16-HS32.
  5. Caroff SN, Miller DD, Dhopesh V, Campbell C. Is there a rational management strategy for tardive dyskinesia? Curr Psychiatr. 2011;10(10):22-32.
  6. Abdo WF, van de Warrenburg BP, Burn DJ, Quinn NP, Bloem BR. The clinical approach to movement disorders. Nat Rev Neurol. 2010;6(1):29-37.
  7. Mezzich JE, Salloum IM. Clinical complexity and person-centered integrative diagnosis. World Psychiatry. 2008;7(1):1-2.
  8. Totah N, Akil H, Huys QJM, et al. Complexity and heterogeneity in psychiatric disorders. In: Redish AD, Gordon JA, eds. Computational Psychiatry: New Perspectives on Mental Illness. Cambridge, MA: MIT Press; 2016:33-59.
  9. Aquino CC, Lang AE. Tardive dyskinesia syndromes: current concepts. Parkinsonism Relat Disord. 2014;20(Suppl 1):S113-S117.
  10. Lerner PP, Miodownik C, Lerner V. Tardive dyskinesia (syndrome): Current concept and modern approaches to its management. Psychiatry Clin Neurosci. 2015;69:321-334.
  11. Cloud LJ, Zutshi D, Factor SA. Tardive dyskinesia: therapeutic options for an increasingly common disorder. Neurotherapeutics. 2014;11(1):166-176.
  12. Karadayi G, Emiroglu B, Ucok A. Relationship of symptomatic remission with quality of life and functionality in patients with schizophrenia. Compr Psychiatry. 2011;52(6):701-707.
  13. Bhidayasiri R, Fahn S, Weiner WJ, Gronseth GS, Sullivan KL, Zesiewicz TA. Evidence-based guideline: treatment of tardive syndromes: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;81(5):463-469.
  1. Summary of evidence-based guideline for clinicians: Treatment of tardive syndromes. 2013. American Academy of Neurology website. https://www.aan.com/Guidelines/Home/GetGuidelineContent/613. Accessed April 9, 2017.
  2. Lehman AF, Lieberman JA, Dixon LB, et al; American Psychiatric Association; Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2 Suppl):1-56.
  3. Daniel SJ, Kannan PP, Malaiappan M, Anandan H. Relationship between awareness of tardive dyskinesia and awareness of illness in schizophrenia. Int J Sci Stud. 2016;4(7):17-20.
  4. Gharabawi GM, Bossie CA, Lasser RA, Turkoz I, Rodriguez S, Chouinard G. Abnormal Involuntary Movement Scale (AIMS) and Extrapyramidal Symptom Rating Scale (ESRS): crossscale comparison in assessing tardive dyskinesia. Schizophr Res. 2005;77(2-3):119-128.
  5. Lumetti S, Ghiacci G, Macaluso GM, et al. Tardive dyskinesia, oral parafunction, and implant-supported rehabilitation. Case Rep Dent. 2016;2016:7167452.
  6. Glazer WM, Moore DC, Schooler NR, Brenner LM, Morgenstern H. Tardive dyskinesia. A discontinuation study. Arch Gen Psychiatry. 1984;41(6):623-627.
  7. Carbon M, Hsieh CH, Kane JM, Correll CU. Tardive dyskinesia prevalence in the period of second-generation antipsychotic use: A meta-analysis. J Clin Psychiatry. 2017;78(3):e264-e278.
  8. Remington G. Tardive dyskinesia: eliminated, forgotten, or overshadowed? Curr Opin Psychiatry. 2007;20(2):131-137.
  9. Widschwendter CG, Karayal ON, Kolluri S, Vanderburg D, Kemmler G, Fleischhacker WW. Relating spontaneously reported extrapyramidal adverse events to movement disorder rating scales. Int J Neuropsychopharmacol. 2015;18(12).pii:pyv064.
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