Tardive Dyskinesia

Epidemiology

Definition

  • Tardive Dyskinesia is Clinically Distinguished from Acute Dyskinesia, Parkinsonism, and Akathisia (Which Occur Soon After Exposure to Antipsychotic Medications/Metoclopramide)
    • “Tardive” = Occurs Later

Incidence

  • Incidence of Tardive Dyskinesia with Conventional Antipsychotics: 3-8% (J Clin Psychiatry, 2000) [MEDLINE]
  • Age of Patient: tardive dyskinesia is far more common in adults than in children
    • Tardive Dyskinesia Symptoms Occurring in Children May Appear Immediately After Withdrawal of Antipsychotic Agent (and Therefore, Have Been Termed “Withdrawal Emergent Symptoms”)

Risk Factors

  • Advanced Age: most common risk factor
  • Less Clearly-Associated Risk Factors
    • African-American Race
    • Brain Damage
    • Dementia (see Dementia, [[Dementia]])
    • Diabetes Mellitus (DM) (see Diabetes Mellitus, [[Diabetes Mellitus]])
    • Duration of Antipsychotic Drug Exposure
    • Female Sex
    • History of Electroconvulsive Therapy (ECT)
    • History of Prior Extrapyramidal Reaction to Antipsychotic Agent
    • Major Affective Disorder
    • Use of Anticholinergic/Antiparkinson Agents

Etiology

Drugs

  • First-Generation Antipsychotic Agents
    • General Comments
      • First-Generation Antipsychotic Agents Have a Higher Incidence of Extrapyramidal Adverse Effects and Tardive Dyskinesia, as Compared to the Second-Generation Antipsychotic Agents
    • Low-Potency Agents: higher anticholinergic side effects, lower extrapyramidal side effects
      • Chlorpromazine (Largactil, Thorazine) (see Chlorpromazine, [[Chlorpromazine]])
      • Thioridazine (Mellaril, Novoridazine, Thioril) (see Thioridazine, [[Thioridazine]])
    • High-Potency Agents: lower anticholinergic side effects, higher extrapyramidal side effects
      • Fluphenazine (XXX) (see Fluphenazine, [[Fluphenazine]])
      • Haloperidol (Haldol) (see Haloperidol, [[Haloperidol]])
      • Loxapine (XXX) (see Loxapine, [[Loxapine]])
      • Perphenazine (Trilafon) (see Perphenazine, [[Perphenazine]])
      • Pimozide (XXX) (see Pimozide, [[Pimozide]])
      • Thiothixene (XXX) (see Thiothixene, [[Thiothixene]])
      • Trifluoperazine (Stelazine) (see Trifluoperazine, [[Trifluoperazine]])
  • Second-Generation Antipsychotic Agents (Atypical Antipsychotics)
    • General Comments
      • Second-Generation Antipsychotic Agents are Generally Believed to Have a Lower Incidence of Extrapyramidal Adverse Effects and Tardive Dyskinesia, as Compared to the First-Generation Antipsychotic Agents: likely related to the weaker affinity of these agents for the dopamine D2 receptor
      • However, Other Studies Have Suggested that the Differences Between First and Second-Generation Antipsychotics with Regard to Extrapyramidal Side Effects May Be More Minimal than Has Been Previously Believed (Lancet, 2003) [MEDLINE]
    • Aripiprazole (Ability) (see Aripiprazole, [[Aripiprazole]])
    • Asenapine (see Asenapine, [[Asenapine]])
    • Brexpiprazole (XXX) (see Brexpiprazole, [[Brexpiprazole]])
    • Cariprazine (see Cariprazine, [[Cariprazine]])
    • Clozapine (Clozaril) (see Clozapine, [[Clozapine]])
      • Epidemiology: clozapine has a low risk of acute extrapyramidal effects, as well as a rare association with tardive dyskinesia
    • Iloperidone (XXX) (see Iloperidone, [[Iloperidone]])
    • Lurasidone (Latuda) (see Lurasidone, [[Lurasidone]])
    • Olanzapine (Zyprexa) (see Olanzapine, [[Olanzapine]])
      • Epidemiology: highest risk of tardive dyskinesia among the second-generation antipsychotics
    • Paliperidone (XXX) (see Paliperidone, [[Paliperidone]])
    • Pimavanserin (XXX) (see Pimavanserin, [[Pimavanserin]])
    • Quetiapine (Seroquel) (see Quetiapine, [[Quetiapine]])
    • Risperidone (Risperdal) (see Risperidone, [[Risperidone]])
      • Epidemiology: highest risk of tardive dyskinesia among the second-generation antipsychotics
    • Ziprasidone (Geodon) (see Ziprasidone, [[Ziprasidone]])
  • Metoclopramide (Reglan) (see Metoclopramide, [[Metoclopramide]])
    • Epidemiology
      • Average Duration of Use Prior to the Onset Metoclopramide-Induced Movement Disorders is 1 Year (Range: 1 Day-4 Years), with Therapy Continued an Average of 6 mo After the Onset of Symptoms (Arch Intern Med, 1989) [MEDLINE]: data suggest that association of the movement disorder with the use of metoclopramide was not initially clinically recognized
      • Portland VA Pharmacy Study of Relative Risk of Movement Disorders with the Use of Metoclopramide (Arch Intern Med, 1993) [MEDLINE]
        • Relative Risk of Tardive Dyskinesia with Metoclopramide is 1.67 (95% CI: 0.93-2.97)
        • Relative Risk of Drug-Induced Parkinsonism with Metoclopramide is 4.0 (95% CI: 1.5-10.5 )
      • Risk Factors for Metoclopramide-Induced Movement Disorders (Nat Clin Pract Gastroenterol Hepatol, 2006) [MEDLINE]
      • Review Suggests that the Risk of Metoclopramide-Associated Tardive Dyskinesia was <1% (Aliment Pharmacol Ther, 2010) [MEDLINE]: tardive dyskinesia may occur idiosyncratically
        • Case Reports Have Identified Metoclopramide-Associated Tardive Dyskinesia After Short-Term Use in Younger Patients (Int J Clin Pharm, 2012) [MEDLINE]
      • FDA Issued a Black Box Warning in 2008 Regarding Long-Term/High-Dose Metoclopramide Use [MEDLINE]
      • Black Box Warning Regarding Metoclopramide-Associated Tardive Dyskinesia Has Decreased its Usage and Increased Rates of Adverse Event Reporting (Am J Gastroenterol, 2013) [MEDLINE]
    • Physiology
      • Antagonism at Central Nervous System Dopamine D1 and D2 Receptors
      • Antagonism at Serotonin Receptors: at high dose

Physiology

Potential Mechanisms of Antipsychotic-Associated Extrapyramidal Adverse Effects and Tardive Dyskinesia

  • Blockade of Postsynaptic Dopamine Receptors
    • In Animal Models, Repeated Exposure to Antipsychotic Agents Results in Supersensitivity of Dopamine Receptors (Neuropharmacology, 1974) [MEDLINE] and (Annu Rev Med, 1984) [MEDLINE]
    • In Humans, Chronic Antipsychotic Exposure Results in Upregulation of Striatal Dopamine Receptors (Nature, 1978) [MEDLINE]
  • Imbalance Between Dopamine D1 and D2 Receptor-Mediated Effects in the Basal Ganglia
    • First-Generation Antipsychotics Preferentially Block D2 Receptors, Resulting in Excessive D1-Mediated Striatopallidal Output, Altering Firing in the Medical Globus Pallidus
  • Loss of Striatal Interneurons (Which Use GABA, Acetylcholine, or Peptides) Which Exert Feedback on Nigrostriatal Dopamine Neurons

Diagnosis

XXX

  • xxxxx

Clinical Manifestations

General Comments

  • Time of Onset of Symptoms: tardive dyskinesia may occur as early within 1 mo-6 mo after initiation of agent (older literature suggested that onset occurred only after 1-2 yrs of treatment)
  • Relationship to Change in Dose: tardive dyskinesia may first occur after a reduction in dose, after switching to a lower potency agent, or following discontinuation of the agent
  • Severity of Tardive Dyskinesa Varies with the Degree of Behavioral/Emotional Arousal

Neurologic Manifestations

  • General Comments
    • Anatomic Distribution of Neurologic Symptoms
      • Extremities
      • Face
      • Mouth
      • Tongue
      • Trunk
  • Athetosis (see Athetosis, [[Athetosis]])
  • Chorea (see Chorea, [[Chorea]])
  • Extremity Dyskinesia: typically more severe in younger patients
    • Ballismus (see Ballismus, [[Ballismus]]): typically more severe in younger patients
    • Dystonic Extensor Posture of Toes
    • Foot Tapping Movement
    • Twisting, Spreading, and/or “Piano Playing” Finger Movements
  • Increased Frequency of Blinking: may occur early in the course
  • Neck/Trunk Dyskinesia: truncal dyskinesia may interfere with gait/ambulation
    • Axial Dystonia
    • Retrocollis
    • Rocking/Swaying Movement
    • Rotatory/Thrusting Hip Movement
    • Shoulder Shrugging
    • Torticollis (see Torticollis, [[Torticollis]])
  • Orofacial/Lingual Dyskinesia: may interfere with breathing, speech, and eating/swallowing
    • Blepharospasm (see Blepharospasm, [[Blepharospasm]])
    • Bulging of the Cheeks
    • Chewing Movements
    • Facial Grimacing
    • Facial Tics
    • Pouting/Puckering/Smacking Movement of Lips
    • Protruding/Twisting Movement of Tongue
    • Retraction of Corners of the Mouth
  • Tardive Akathisia (see Akathisia, [[Akathisia]]): this is clinically distinguished from acute akathisia, owing to its appearance late after exposure to the agent and the presence of dyskinesia/absence of subjective motor restlessness
  • Tardive Dystonia (see Dystonia, [[Dystonia]]): occurs more commonly in patients <40 y/o
    • Blepharospasm (see Blepharospasm, [[Blepharospasm]])
    • Extremity Hyperextension
    • Jaw Dystonia
    • Opisthotonos (Opisthotonus) (see Opisthotonos, [[Opisthotonos]])
    • Retrocollis
    • Shoulder Dystonia
  • Tardive Myoclonus (see Myoclonus, [[Myoclonus]]): rare
  • Tardive Stereotypy: stereotyped behaviors
  • Tardive Tremor (see Tremor, [[Tremor]])
    • Epidemiology: rare manifestation

Respiratory Manifestations

  • Respiratory Dyskinesia (Chest, 1994) [MEDLINE]
    • Clinical
      • Grunting (see Grunting, [[Grunting]])
      • Irregular Breathing Pattern
        • Respiratory Variability is Less During Sleep
        • Respiratory Variability Does Not Limit Exercise Performance
      • Tachypnea with Low Tidal Volume (see Tachypnea, [[Tachypnea]])

Prevention

Antipsychotic Agents

  • Cautious Use of Antipsychotics for Periods >3 mo
    • Patient Should Be Carefully Monitored and Use of these Agents Periodically Reevaluated: especially in female patients and patients >50 y/o
  • Use the Lowest Effective Antipsychotic Dose
  • Except for the Prevention of Acute Dystonic Reactions, Long-Term Prophylactic Anticholinergic Agents Should Be Avoided, Since These Adjunctive Agents Do Not Prevent Tardive Dyskinesia and They May Exacerbate the Involuntary Movements of Tardive Dyskinesia Once They Occur
  • Avoid Prolonged Use of Antipsychotics in Conditions Such as Depression, Neurosis, Anxiety, Personality Disorder, and Chronic Pain Syndrome

Metoclopramide (Reglan) (see Metoclopramide, [[Metoclopramide]])

  • Avoidance of Use of Metoclopramide (Reglan) for >12 wlks

Treatment

General Measures

  • Once Tardive Dyskinesia Occurs with an Antipsychotic Agent, Prompt Withdrawal of the Agent Improves the Probability of Recovery
    • Taper and Discontinue as Soon as the Diagnosis of Tardive Dyskinesia is Made
    • If a First-Generation Antipsychotic Agent is Being Used at the Time of Diagnosis of Tardive Dyskinesia and Ongoing Therapy is Required for Psychosis, Switching to a Second-Generation Antipsychotic is Acceptable: however, there is no evidence that this change will alter the clinical course of tardive dyskinesia once it has started
  • Tardive Dyskinesia Associated with Metoclopramide Merits Immediate Discontinuation

Pharmacologic Therapy

Amantadine (Symmetrel) (see Amantadine, [[Amantadine]])

  • xxx

Anticholinergic Agents

Benzodiazepines (see Benzodiazepines, [[Benzodiazepines]])

  • xxx

Botulinum Toxin (see Botulinum Toxin, [[Botulinum Toxin]])

  • xxxx

Cholinergic Agents

  • xxx

Gingko Biloba Extract (see Gingko Biloba, [[Gingko Biloba]])

  • xxx

Vesicular Monamine Transporter 2 Inhibitors

  • Deutetrabenazine
  • Tetrabenazine (Nitoman, Xenazine) (see Tetrabenazine, [[Tetrabenazine]])
    • Pharmacology: vesicular monoamine transporter 2 inhibitors which deplete presynaptic dopamine stores
    • Clinical Efficacy
      • xxxx
  • Valbenazine (Ingrezza) (see Valbenazine, [[Valbenazine]])
    • Pharmacology: vesicular monoamine transporter 2 inhibitors which deplete presynaptic dopamine stores
    • Clinical Efficacy
      • KINECT 3 Trial of Valbenazine In Treatment of Tardive Dyskinesia (Am J Psychiatry, 2017) [MEDLINE]
        • Valbenazine Improved Tardive Dyskinesia in Patients with Underlying Schizophrenia, Schizoaffective Disorder, and Mood Disorder

Vitamin E (see Vitamin E, [[Vitamin E]])

  • xxx

Prognosis

  • Tardive Dyskinesia is Often Reversible
    • Remission Usually Occurs within Several Months, But May Take as Long as 1-3 Years After Withdrawal of the Agent (Annu Rev Med, 1984) [MEDLINE]
  • Medical-Legal Implications
    • Drug-Associated Tardive Dyskinesia Has Significant Medical-Legal Implications (J Clin Psychopharmacol, 1988) [MEDLINE]: patients should be thoroughly informed of tardive dyskinesia as a potential outcome and instructed to maintain appropriate clinical monitoring

References

General

Miscellaneous

  • History and definition of tardive dyskinesia. Clin Neuropharmacol. 1983;6(2):91 [MEDLINE]
  • Malpractice and tardive dyskinesia: a conceptual dilemma. J Clin Psychopharmacol. 1988;8(4 Suppl):71S [MEDLINE]

Antipsychotics

  • Behavioural supersensitivity to apomorphine following chronic treatment with drugs which interfere with the synaptic function of catecholamines. Neuropharmacology. 1974;13(10-11):927 [MEDLINE]
  • Binding of 3H-neuroleptics and 3H-apomorphine in schizophrenic brains. Nature. 1978;274(5674):897 [MEDLINE]
  • Tardive dyskinesia: prevalence and risk factors, 1959 to 1979. Arch Gen Psychiatry. 1982;39(4):473 [MEDLINE]
  • A prospective study of tardive dyskinesia development: preliminary results. J Clin Psychopharmacol. 1982;2(5):345 [MEDLINE]
  • Tardive dyskinesia. Annu Rev Med. 1984;35:605 [MEDLINE]
  • Integrating incidence and prevalence of tardive dyskinesia. Psychopharmacol Bull. 1986;22(1):254 [MEDLINE]
  • Review of incidence studies of tardive dyskinesia associated with typical antipsychotics. J Clin Psychiatry. 2000;61 Suppl 4:15 [MEDLINE]
  • New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet. 2003;361(9369):1581 [MEDLINE]
  • CATIE Trial. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209. Epub 2005 Sep 19 [MEDLINE]
  • Modern antipsychotic drugs: a critical overview. CMAJ. 2005;172(13):1703 [MEDLINE]

Metoclopramide (Reglan) (see Metoclopramide, [[Metoclopramide]])

  • Metoclopramide-induced movement disorders. Clinical findings with a review of the literature. Arch Intern Med. 1989;149(11):2486 [MEDLINE]
  • The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders. Arch Intern Med. 1993;153(12):1469 [MEDLINE]
  • Metoclopramide and tardive dyskinesia. Biol Psychiatry. 1994;36(9):630 [MEDLINE]
  • Drug Insight: from disturbed motility to disordered movement–a review of the clinical benefits and medicolegal risks of metoclopramide. Nat Clin Pract Gastroenterol Hepatol. 2006;3(3):138 [MEDLINE]
  • Metoclopramide, an increasingly recognized cause of tardive dyskinesia. J Clin Pharmacol. 2008;48(3):379. Epub 2008 Jan 25 [MEDLINE]
  • Review article: metoclopramide and tardive dyskinesia. Aliment Pharmacol Ther. 2010 Jan;31(1):11-9. doi: 10.1111/j.1365-2036.2009.04189.x [MEDLINE]
  • Tardive dyskinesia after short-term treatment with oral metoclopramide in an adolescent. Int J Clin Pharm. 2012 Dec;34(6):822-4. doi: 10.1007/s11096-012-9685-4. Epub 2012 Aug 9 [MEDLINE]
  • Metoclopramide-induced tardive respiratory dyskinesia. J Neuropsychiatry Clin Neurosci. 2012 Summer;24(3):E37-8. doi: 10.1176/appi.neuropsych.11070174 [MEDLINE]
  • The metoclopramide black box warning for tardive dyskinesia: effect on clinical practice, adverse event reporting, and prescription drug lawsuits. Am J Gastroenterol. 2013 Jun;108(6):866-72. doi: 10.1038/ajg.2012.300 [MEDLINE]
  • FDA Package Insert [MEDLINE]

Clinical

  • Respiratory dysrhythmias in patients with tardive dyskinesia. Chest. 1994 Jan;105(1):203-7 [MEDLINE]
  • Neuroleptic-induced respiratory dyskinesia. J Neuropsychiatry Clin Neurosci. 1995 Spring;7(2):223-9 [MEDLINE]
  • Prevalence of and risk factors for respiratory dyskinesia. Clin Neuropharmacol. 1996 Oct;19(5):390-8 [MEDLINE]
  • Multiple rib fractures secondary to severe tardive dystonia and respiratory dyskinesia. J Clin Psychiatry. 2000 Mar;61(3):215-6 [MEDLINE]
  • Respiratory dyskinesia–an under-recognized side-effect of neuroleptic medications. Pak Med Assoc. 2011 Sep;61(9):930-2 [MEDLINE]
  • Metoclopramide-induced tardive respiratory dyskinesia. J Neuropsychiatry Clin Neurosci. 2012 Summer;24(3):E37-8. doi: 10.1176/appi.neuropsych.11070174 [MEDLINE]
  • Tardive tachypnea. Intensive Care Med. 2016 Dec;42(12):2126. doi: 10.1007/s00134-016-4555-5. Epub 2016 Oct 3 [MEDLINE]

Prevention

  • Tardive dyskinesia: summary of a Task Force Report of the American Psychiatric Association. By the Task Force on Late Neurological Effects of Antipsychotic Drugs. Am J Psychiatry. 1980;137(10):1163 [MEDLINE]

Treatment

  • KINECT 3: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Valbenazine for Tardive Dyskinesia. Am J Psychiatry. 2017;174(5):476. Epub 2017 Mar 21 [MEDLINE]