Tardive Dyskinesia

<h2>Epidemiology</h2>

<h3>Definition</h3>

<ul>

<li><b>Tardive Dyskinesia is Clinically Distinguished from Acute Dyskinesia, Parkinsonism, and Akathisia (Which Occur Soon After Exposure to Antipsychotic Medications/Metoclopramide)</b>

<ul>

<li><em>&ldquo;Tardive&rdquo;</em> = Occurs Later</li>

</ul>

</li>

</ul>

<h3>Incidence</h3>

<ul>

<li><b>Incidence of Tardive Dyskinesia with Conventional Antipsychotics</b>: 3-8% (J Clin Psychiatry, 2000) [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/10739326″ title=”MEDLINE”>MEDLINE</a>]</li>

<li><b>Age of Patient</b>: tardive dyskinesia is far more common in adults than in children

<ul>

<li><em>Tardive Dyskinesia Symptoms Occurring in Children May Appear Immediately After Withdrawal of Antipsychotic Agent (and Therefore, Have Been Termed &ldquo;Withdrawal Emergent Symptoms&rdquo;)</em></li>

</ul>

</li>

</ul>

<h3>Risk Factors</h3>

<ul>

<li><b>Advanced Age</b>: most common risk factor</li>

<li><b>Less Clearly-Associated Risk Factors</b>

<ul>

<li><em>African-American Race</em></li>

<li><em>Brain Damage</em></li>

<li><em>Dementia</em> (see <a href=”http://mdnxs.com/topics-2/neurology/dementia/” title=”Dementia”>Dementia</a>, <a href=’/Dementia’ class=’wiki-link ‘>Dementia</a>)</li>

<li><em>Diabetes Mellitus (DM)</em> (see <a href=”http://mdnxs.com/topics-2/endocrinology/diabetes-mellitus/” title=”Diabetes Mellitus”>Diabetes Mellitus</a>, <a href=’/DiabetesMellitus’ class=’wiki-link ‘>Diabetes Mellitus</a>)</li>

<li><em>Duration of Antipsychotic Drug Exposure</em></li>

<li><em>Female Sex</em></li>

<li><em>History of Electroconvulsive Therapy (ECT)</em></li>

<li><em>History of Prior Extrapyramidal Reaction to Antipsychotic Agent</em></li>

<li><em>Major Affective Disorder</em></li>

<li><em>Use of Anticholinergic/Antiparkinson Agents</em></li>

</ul>

</li>

</ul>

<hr />

<h2>Etiology</h2>

<h3>Drugs</h3>

<ul>

<li><b>First-Generation Antipsychotic Agents</b>

<ul>

<li><em>General Comments</em>

<ul>

<li>First-Generation Antipsychotic Agents Have a Higher Incidence of Extrapyramidal Adverse Effects and Tardive Dyskinesia, as Compared to the Second-Generation Antipsychotic Agents</li>

</ul>

</li>

<li><em>Low-Potency Agents</em>: higher anticholinergic side effects, lower extrapyramidal side effects

<ul>

<li>Chlorpromazine (Largactil, Thorazine) (see <a href=”http://mdnxs.com/topics-2/pharmacology/chlorpromazine/” title=”Chlorpromazine”>Chlorpromazine</a>, <a href=’/Chlorpromazine’ class=’wiki-link ‘>Chlorpromazine</a>)</li>

<li>Thioridazine (Mellaril, Novoridazine, Thioril) (see <a href=”http://mdnxs.com/topics-2/pharmacology/thioridazine/” title=”Thioridazine”>Thioridazine</a>, <a href=’/Thioridazine’ class=’wiki-link ‘>Thioridazine</a>)</li>

</ul>

</li>

<li><em>High-Potency Agents</em>: lower anticholinergic side effects, higher extrapyramidal side effects

<ul>

<li>Fluphenazine (XXX) (see <a href=”http://mdnxs.com/topics-2/pharmacology/fluphenazine/” title=”Fluphenazine”>Fluphenazine</a>, <a href=’/Fluphenazine’ class=’wiki-link ‘>Fluphenazine</a>)</li>

<li>Haloperidol (Haldol) (see <a href=”http://mdnxs.com/topics-2/pharmacology/haloperidol/” title=”Haloperidol”>Haloperidol</a>, <a href=’/Haloperidol’ class=’wiki-link ‘>Haloperidol</a>)</li>

<li>Loxapine (XXX) (see <a href=”http://mdnxs.com/topics-2/pharmacology/loxapine/” title=”Loxapine”>Loxapine</a>, <a href=’/Loxapine’ class=’wiki-link ‘>Loxapine</a>)</li>

<li>Perphenazine (Trilafon) (see <a href=”http://mdnxs.com/topics-2/pharmacology/perphenazine/” title=”Perphenazine”>Perphenazine</a>, <a href=’/Perphenazine’ class=’wiki-link ‘>Perphenazine</a>)</li>

<li>Pimozide (XXX) (see <a href=”http://mdnxs.com/topics-2/pharmacology/pimozide/” title=”Pimozide”>Pimozide</a>, <a href=’/Pimozide’ class=’wiki-link missing-wiki-link’>Pimozide</a>)</li>

<li>Thiothixene (XXX) (see <a href=”http://mdnxs.com/topics-2/pharmacology/thiothixene/” title=”Thiothixene”>Thiothixene</a>, <a href=’/Thiothixene’ class=’wiki-link missing-wiki-link’>Thiothixene</a>)</li>

<li>Trifluoperazine (Stelazine) (see <a href=”http://mdnxs.com/topics-2/pharmacology/trifluoperazine/” title=”Trifluoperazine”>Trifluoperazine</a>, <a href=’/Trifluoperazine’ class=’wiki-link ‘>Trifluoperazine</a>)</li>

</ul>

</li>

</ul>

</li>

<li><b>Second-Generation Antipsychotic Agents (Atypical Antipsychotics)</b>

<ul>

<li><em>General Comments</em>

<ul>

<li>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</li>

<li>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) [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/12747876″ title=”MEDLINE”>MEDLINE</a>]</li>

</ul>

</li>

<li><em>Aripiprazole (Ability)</em> (see <a href=”http://mdnxs.com/topics-2/pharmacology/aripiprazole/” title=”Aripiprazole”>Aripiprazole</a>, <a href=’/Aripiprazole’ class=’wiki-link ‘>Aripiprazole</a>)</li>

<li><em>Asenapine</em> (see <a href=”http://mdnxs.com/topics-2/pharmacology/asenapine/” title=”Asenapine”>Asenapine</a>, <a href=’/Asenapine’ class=’wiki-link ‘>Asenapine</a>)</li>

<li><em>Brexpiprazole (XXX)</em> (see <a href=”http://mdnxs.com/topics-2/pharmacology/brexpiprazole/” title=”Brexpiprazole”>Brexpiprazole</a>, <a href=’/Brexpiprazole’ class=’wiki-link missing-wiki-link’>Brexpiprazole</a>)</li>

<li><em>Cariprazine</em> (see <a href=”http://mdnxs.com/topics-2/pharmacology/cariprazine/” title=”Cariprazine”>Cariprazine</a>, <a href=’/Cariprazine’ class=’wiki-link missing-wiki-link’>Cariprazine</a>)</li>

<li><em>Clozapine (Clozaril)</em> (see <a href=”http://mdnxs.com/topics-2/pharmacology/clozapine/” title=”Clozapine”>Clozapine</a>, <a href=’/Clozapine’ class=’wiki-link ‘>Clozapine</a>)

<ul>

<li>Epidemiology: clozapine has a low risk of acute extrapyramidal effects, as well as a rare association with tardive dyskinesia</li>

</ul>

</li>

<li><em>Iloperidone (XXX)</em> (see <a href=”http://mdnxs.com/topics-2/pharmacology/iloperidone/” title=”Iloperidone”>Iloperidone</a>, <a href=’/Iloperidone’ class=’wiki-link missing-wiki-link’>Iloperidone</a>)</li>

<li><em>Lurasidone (Latuda)</em> (see <a href=”http://mdnxs.com/topics-2/pharmacology/lurasidone/” title=”Lurasidone”>Lurasidone</a>, <a href=’/Lurasidone’ class=’wiki-link ‘>Lurasidone</a>)</li>

<li><em>Olanzapine (Zyprexa)</em> (see <a href=”http://mdnxs.com/topics-2/pharmacology/olanzapine/” title=”Olanzapine”>Olanzapine</a>, <a href=’/Olanzapine’ class=’wiki-link ‘>Olanzapine</a>)

<ul>

<li>Epidemiology: highest risk of tardive dyskinesia among the second-generation antipsychotics</li>

</ul>

</li>

<li><em>Paliperidone (XXX)</em> (see <a href=”http://mdnxs.com/topics-2/pharmacology/paliperidone/” title=”Paliperidone”>Paliperidone</a>, <a href=’/Paliperidone’ class=’wiki-link missing-wiki-link’>Paliperidone</a>)</li>

<li><em>Pimavanserin (XXX)</em> (see <a href=”http://mdnxs.com/topics-2/pharmacology/pimavanserin/” title=”Pimavanserin”>Pimavanserin</a>, <a href=’/Pimavanserin’ class=’wiki-link missing-wiki-link’>Pimavanserin</a>)</li>

<li><em>Quetiapine (Seroquel)</em> (see <a href=”http://mdnxs.com/topics-2/pharmacology/quetiapine/” title=”Quetiapine”>Quetiapine</a>, <a href=’/Quetiapine’ class=’wiki-link ‘>Quetiapine</a>)</li>

<li><em>Risperidone (Risperdal)</em> (see <a href=”http://mdnxs.com/topics-2/pharmacology/risperidone/” title=”Risperidone”>Risperidone</a>, <a href=’/Risperidone’ class=’wiki-link ‘>Risperidone</a>)

<ul>

<li>Epidemiology: highest risk of tardive dyskinesia among the second-generation antipsychotics</li>

</ul>

</li>

<li><em>Ziprasidone (Geodon)</em> (see <a href=”http://mdnxs.com/topics-2/pharmacology/ziprasidone/” title=”Ziprasidone”>Ziprasidone</a>, <a href=’/Ziprasidone’ class=’wiki-link ‘>Ziprasidone</a>)</li>

</ul>

</li>

<li><b>Metoclopramide (Reglan)</b> (see <a href=”http://mdnxs.com/topics-2/pharmacology/metoclopramide/” title=”Metoclopramide”>Metoclopramide</a>, <a href=’/Metoclopramide’ class=’wiki-link ‘>Metoclopramide</a>)

<ul>

<li><em>Epidemiology</em>

<ul>

<li>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) [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/2684075″ title=”MEDLINE”>MEDLINE</a>]: data suggest that association of the movement disorder with the use of metoclopramide was not initially clinically recognized</li>

<li>Portland VA Pharmacy Study of Relative Risk of Movement Disorders with the Use of Metoclopramide (Arch Intern Med, 1993) [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/8512437″ title=”MEDLINE”>MEDLINE</a>]

<ul>

<li>Relative Risk of Tardive Dyskinesia with Metoclopramide is 1.67 (95% CI: 0.93-2.97)</li>

<li>Relative Risk of Drug-Induced Parkinsonism with Metoclopramide is 4.0 (95% CI: 1.5-10.5 )</li>

</ul>

</li>

<li>Risk Factors for Metoclopramide-Induced Movement Disorders (Nat Clin Pract Gastroenterol Hepatol, 2006) [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/16511548″ title=”MEDLINE”>MEDLINE</a>]

<ul>

<li>Age</li>

<li>Female Sex</li>

<li>Diabetes Mellitus (see <a href=”http://mdnxs.com/topics-2/endocrinology/diabetes-mellitus/” title=”Diabetes Mellitus”>Diabetes Mellitus</a>, <a href=’/DiabetesMellitus’ class=’wiki-link ‘>Diabetes Mellitus</a>)</li>

</ul>

</li>

<li>Review Suggests that the Risk of Metoclopramide-Associated Tardive Dyskinesia was &lt;1% (Aliment Pharmacol Ther, 2010) [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/19886950″ title=”MEDLINE”>MEDLINE</a>]: tardive dyskinesia may occur idiosyncratically

<ul>

<li>Case Reports Have Identified Metoclopramide-Associated Tardive Dyskinesia After Short-Term Use in Younger Patients (Int J Clin Pharm, 2012) [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/22875741″ title=”MEDLINE”>MEDLINE</a>]</li>

</ul>

</li>

<li>FDA Issued a Black Box Warning in 2008 Regarding Long-Term/High-Dose Metoclopramide Use [<a href=”https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017854s062lbl.pdf” title=”MEDLINE”>MEDLINE</a>]</li>

<li>Black Box Warning Regarding Metoclopramide-Associated Tardive Dyskinesia Has Decreased its Usage and Increased Rates of Adverse Event Reporting (Am J Gastroenterol, 2013) [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/23735907″ title=”MEDLINE”>MEDLINE</a>]</li>

</ul>

</li>

<li><em>Physiology</em>

<ul>

<li>Antagonism at Central Nervous System Dopamine D1 and D2 Receptors</li>

<li>Antagonism at Serotonin Receptors: at high dose</li>

</ul>

</li>

</ul>

</li>

</ul>

<hr />

<h2>Physiology</h2>

<h3>Potential Mechanisms of Antipsychotic-Associated Extrapyramidal Adverse Effects and Tardive Dyskinesia</h3>

<ul>

<li><b>Blockade of Postsynaptic Dopamine Receptors</b>

<ul>

<li><em>In Animal Models, Repeated Exposure to Antipsychotic Agents Results in Supersensitivity of Dopamine Receptors (Neuropharmacology, 1974) [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/4474641″ title=”MEDLINE”>MEDLINE</a>] and (Annu Rev Med, 1984)</em> [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/6144288″ title=”MEDLINE”>MEDLINE</a>]</li>

<li><em>In Humans, Chronic Antipsychotic Exposure Results in Upregulation of Striatal Dopamine Receptors (Nature, 1978)</em> [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/683328″ title=”MEDLINE”>MEDLINE</a>]</li>

</ul>

</li>

<li><b>Imbalance Between Dopamine D1 and D2 Receptor-Mediated Effects in the Basal Ganglia</b>

<ul>

<li><em>First-Generation Antipsychotics Preferentially Block D2 Receptors, Resulting in Excessive D1-Mediated Striatopallidal Output, Altering Firing in the Medical Globus Pallidus</em></li>

</ul>

</li>

<li><b>Loss of Striatal Interneurons (Which Use GABA, Acetylcholine, or Peptides) Which Exert Feedback on Nigrostriatal Dopamine Neurons</b></li>

</ul>

<hr />

<h2>Diagnosis</h2>

<h3>XXX</h3>

<ul>

<li><b>xxxxx</b></li>

</ul>

<hr />

<h2>Clinical Manifestations</h2>

<h3>General Comments</h3>

<ul>

<li><b>Time of Onset of Symptoms</b>: 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)</li>

<li><b>Relationship to Change in Dose</b>: tardive dyskinesia may first occur after a reduction in dose, after switching to a lower potency agent, or following discontinuation of the agent</li>

<li><b>Severity of Tardive Dyskinesa Varies with the Degree of Behavioral/Emotional Arousal</b></li>

</ul>

<h3>Neurologic Manifestations</h3>

<ul>

<li><b>General Comments</b>

<ul>

<li><em>Anatomic Distribution of Neurologic Symptoms</em>

<ul>

<li>Extremities</li>

<li>Face</li>

<li>Mouth</li>

<li>Tongue</li>

<li>Trunk</li>

</ul>

</li>

</ul>

</li>

<li><b>Athetosis</b> (see <a href=”http://mdnxs.com/topics-2/neurology/athetosis/” title=”Athetosis”>Athetosis</a>, <a href=’/Athetosis’ class=’wiki-link missing-wiki-link’>Athetosis</a>)</li>

<li><b>Chorea</b> (see <a href=”http://mdnxs.com/topics-2/neurology/chorea/” title=”Chorea”>Chorea</a>, <a href=’/Chorea’ class=’wiki-link ‘>Chorea</a>)</li>

<li><b>Extremity Dyskinesia</b>: typically more severe in younger patients

<ul>

<li><em>Ballismus</em> (see <a href=”http://mdnxs.com/topics-2/neurology/ballismus/” title=”Ballismus”>Ballismus</a>, <a href=’/Ballismus’ class=’wiki-link ‘>Ballismus</a>): typically more severe in younger patients</li>

<li><em>Dystonic Extensor Posture of Toes</em></li>

<li><em>Foot Tapping Movement</em></li>

<li><em>Twisting, Spreading, and/or &ldquo;Piano Playing&rdquo; Finger Movements</em></li>

</ul>

</li>

<li><b>Increased Frequency of Blinking</b>: may occur early in the course</li>

<li><b>Neck/Trunk Dyskinesia</b>: truncal dyskinesia may interfere with gait/ambulation

<ul>

<li><em>Axial Dystonia</em></li>

<li><em>Retrocollis</em></li>

<li><em>Rocking/Swaying Movement</em></li>

<li><em>Rotatory/Thrusting Hip Movement</em></li>

<li><em>Shoulder Shrugging</em></li>

<li><em>Torticollis</em> (see <a href=”http://mdnxs.com/topics-2/neurology/torticollis/” title=”Torticollis”>Torticollis</a>, <a href=’/Torticollis’ class=’wiki-link ‘>Torticollis</a>)</li>

</ul>

</li>

<li><b>Orofacial/Lingual Dyskinesia</b>: may interfere with breathing, speech, and eating/swallowing

<ul>

<li><em>Blepharospasm</em> (see <a href=”http://mdnxs.com/topics-2/ophthalmology/blepharospasm/” title=”Blepharospasm”>Blepharospasm</a>, <a href=’/Blepharospasm’ class=’wiki-link missing-wiki-link’>Blepharospasm</a>)</li>

<li><em>Bulging of the Cheeks</em></li>

<li><em>Chewing Movements</em></li>

<li><em>Facial Grimacing</em></li>

<li><em>Facial Tics</em></li>

<li><em>Pouting/Puckering/Smacking Movement of Lips</em></li>

<li><em>Protruding/Twisting Movement of Tongue</em></li>

<li><em>Retraction of Corners of the Mouth</em></li>

</ul>

</li>

<li><b>Tardive Akathisia</b> (see <a href=”http://mdnxs.com/topics-2/neurology/akathisia/” title=”Akathisia”>Akathisia</a>, <a href=’/Akathisia’ class=’wiki-link ‘>Akathisia</a>): 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</li>

<li><b>Tardive Dystonia</b> (see <a href=”http://mdnxs.com/topics-2/neurology/dystonia/” title=”Dystonia”>Dystonia</a>, <a href=’/Dystonia’ class=’wiki-link ‘>Dystonia</a>): occurs more commonly in patients &lt;40 y/o

<ul>

<li><em>Blepharospasm</em> (see <a href=”http://mdnxs.com/topics-2/ophthalmology/blepharospasm/” title=”Blepharospasm”>Blepharospasm</a>, <a href=’/Blepharospasm’ class=’wiki-link missing-wiki-link’>Blepharospasm</a>)</li>

<li><em>Extremity Hyperextension</em></li>

<li><em>Jaw Dystonia</em></li>

<li><em>Opisthotonos (Opisthotonus)</em> (see <a href=”http://mdnxs.com/topics-2/neurology/opisthotonos/” title=”Opisthotonos”>Opisthotonos</a>, <a href=’/Opisthotonos’ class=’wiki-link ‘>Opisthotonos</a>)</li>

<li><em>Retrocollis</em></li>

<li><em>Shoulder Dystonia</em></li>

</ul>

</li>

<li><b>Tardive Myoclonus</b> (see <a href=”http://mdnxs.com/topics-2/neurology/myoclonus/” title=”Myoclonus”>Myoclonus</a>, <a href=’/Myoclonus’ class=’wiki-link ‘>Myoclonus</a>): rare</li>

<li><b>Tardive Stereotypy</b>: stereotyped behaviors</li>

<li><b>Tardive Tremor</b> (see <a href=”http://mdnxs.com/topics-2/neurology/tremor/” title=”Tremor”>Tremor</a>, <a href=’/Tremor’ class=’wiki-link ‘>Tremor</a>)

<ul>

<li><em>Epidemiology</em>: rare manifestation</li>

</ul>

</li>

</ul>

<h3>Respiratory Manifestations</h3>

<ul>

<li><b>Respiratory Dyskinesia</b> (Chest, 1994) [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/7903923″ title=”MEDLINE”>MEDLINE</a>]

<ul>

<li><em>Clinical</em>

<ul>

<li>Grunting (see <a href=”http://mdnxs.com/topics-2/pulmonary-and-critical-care/grunting/” title=”Grunting”>Grunting</a>, <a href=’/Grunting’ class=’wiki-link missing-wiki-link’>Grunting</a>)</li>

<li>Irregular Breathing Pattern

<ul>

<li>Respiratory Variability is Less During Sleep</li>

<li>Respiratory Variability Does Not Limit Exercise Performance</li>

</ul>

</li>

<li>Tachypnea with Low Tidal Volume (see <a href=”http://mdnxs.com/topics-2/pulmonary-and-critical-care/tachypnea/” title=”Tachypnea”>Tachypnea</a>, <a href=’/Tachypnea’ class=’wiki-link ‘>Tachypnea</a>)</li>

</ul>

</li>

</ul>

</li>

</ul>

<hr />

<h2>Prevention</h2>

<h3>Antipsychotic Agents</h3>

<ul>

<li><b>Cautious Use of Antipsychotics for Periods >3 mo</b>

<ul>

<li><em>Patient Should Be Carefully Monitored and Use of these Agents Periodically Reevaluated</em>: especially in female patients and patients >50 y/o</li>

</ul>

</li>

<li><b>Use the Lowest Effective Antipsychotic Dose</b></li>

<li><b>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</b></li>

<li><b>Avoid Prolonged Use of Antipsychotics in Conditions Such as Depression, Neurosis, Anxiety, Personality Disorder, and Chronic Pain Syndrome</b></li>

</ul>

<h3>Metoclopramide (Reglan) (see <a href=”http://mdnxs.com/topics-2/pharmacology/metoclopramide/” title=”Metoclopramide”>Metoclopramide</a>, <a href=’/Metoclopramide’ class=’wiki-link ‘>Metoclopramide</a>)</h3>

<ul>

<li><b>Avoidance of Use of Metoclopramide (Reglan) for >12 wlks</b></li>

</ul>

<hr />

<h2>Treatment</h2>

<h3>General Measures</h3>

<ul>

<li><b>Once Tardive Dyskinesia Occurs with an Antipsychotic Agent, Prompt Withdrawal of the Agent Improves the Probability of Recovery</b>

<ul>

<li><em>Taper and Discontinue as Soon as the Diagnosis of Tardive Dyskinesia is Made</em></li>

<li><em>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</em>: however, there is no evidence that this change will alter the clinical course of tardive dyskinesia once it has started</li>

</ul>

</li>

<li><b>Tardive Dyskinesia Associated with Metoclopramide Merits Immediate Discontinuation</b></li>

</ul>

<h3>Pharmacologic Therapy</h3>

<h4>Amantadine (Symmetrel) (see <a href=”http://mdnxs.com/topics-2/pharmacology/amantadine/” title=”Amantadine”>Amantadine</a>, <a href=’/Amantadine’ class=’wiki-link ‘>Amantadine</a>)</h4>

<ul>

<li><b>xxx</b></li>

</ul>

<h4>Anticholinergic Agents</h4>

<ul>

<li><b>Agents</b>

<ul>

<li><em>Benztropine (XXX)</em> (see <a href=”http://mdnxs.com/topics-2/pharmacology/benztropine/” title=”Benztropine”>Benztropine</a>, <a href=’/Benztropine’ class=’wiki-link ‘>Benztropine</a>)</li>

<li><em>Trihexyphenidyl (Artane)</em> (see <a href=”http://mdnxs.com/topics-2/pharmacology/trihexyphenidyl/” title=”Trihexyphenidyl”>Trihexyphenidyl</a>, <a href=’/Trihexyphenidyl’ class=’wiki-link ‘>Trihexyphenidyl</a>)</li>

</ul>

</li>

</ul>

<h4>Benzodiazepines (see <a href=”http://mdnxs.com/topics-2/pharmacology/benzodiazepines/” title=”Benzodiazepines”>Benzodiazepines</a>, <a href=’/Benzodiazepines’ class=’wiki-link ‘>Benzodiazepines</a>)</h4>

<ul>

<li><b>xxx</b></li>

</ul>

<h4>Botulinum Toxin (see <a href=”http://mdnxs.com/topics-2/pharmacology/botulinum-toxin/” title=”Botulinum Toxin”>Botulinum Toxin</a>, <a href=’/BotulinumToxin’ class=’wiki-link missing-wiki-link’>Botulinum Toxin</a>)</h4>

<ul>

<li><b>xxxx</b></li>

</ul>

<h4>Cholinergic Agents</h4>

<ul>

<li><b>xxx</b></li>

</ul>

<h4>Gingko Biloba Extract (see <a href=”http://mdnxs.com/topics-2/pharmacology/gingko-biloba/” title=”Gingko Biloba”>Gingko Biloba</a>, <a href=’/GingkoBiloba’ class=’wiki-link missing-wiki-link’>Gingko Biloba</a>)</h4>

<ul>

<li><b>xxx</b></li>

</ul>

<h4>Vesicular Monamine Transporter 2 Inhibitors</h4>

<ul>

<li><b>Deutetrabenazine</b></li>

<li><b>Tetrabenazine (Nitoman, Xenazine)</b> (see <a href=”http://mdnxs.com/topics-2/pharmacology/tetrabenazine/” title=”Tetrabenazine”>Tetrabenazine</a>, <a href=’/Tetrabenazine’ class=’wiki-link ‘>Tetrabenazine</a>)

<ul>

<li><em>Pharmacology</em>: vesicular monoamine transporter 2 inhibitors which deplete presynaptic dopamine stores</li>

<li><em>Clinical Efficacy</em>

<ul>

<li>xxxx</li>

</ul>

</li>

</ul>

</li>

<li><b>Valbenazine (Ingrezza)</b> (see <a href=”http://mdnxs.com/topics-2/pharmacology/valbenazine/” title=”Valbenazine”>Valbenazine</a>, <a href=’/Valbenazine’ class=’wiki-link ‘>Valbenazine</a>)

<ul>

<li><em>Pharmacology</em>: vesicular monoamine transporter 2 inhibitors which deplete presynaptic dopamine stores</li>

<li><em>Clinical Efficacy</em>

<ul>

<li>KINECT 3 Trial of Valbenazine In Treatment of Tardive Dyskinesia (Am J Psychiatry, 2017) [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/28320223″ title=”MEDLINE”>MEDLINE</a>]

<ul>

<li>Valbenazine Improved Tardive Dyskinesia in Patients with Underlying Schizophrenia, Schizoaffective Disorder, and Mood Disorder</li>

</ul>

</li>

</ul>

</li>

</ul>

</li>

</ul>

<h4>Vitamin E (see <a href=”http://mdnxs.com/topics-2/pharmacology/vitamin-e/” title=”Vitamin E”>Vitamin E</a>, <a href=’/VitaminE’ class=’wiki-link ‘>Vitamin E</a>)</h4>

<ul>

<li><b>xxx</b></li>

</ul>

<hr />

<h2>Prognosis</h2>

<ul>

<li><b>Tardive Dyskinesia is Often Reversible</b>

<ul>

<li><em>Remission Usually Occurs within Several Months, But May Take as Long as 1-3 Years After Withdrawal of the Agent (Annu Rev Med, 1984)</em> [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/6144288″ title=”MEDLINE”>MEDLINE</a>]</li>

</ul>

</li>

<li><b>Medical-Legal Implications</b>

<ul>

<li><em>Drug-Associated Tardive Dyskinesia Has Significant Medical-Legal Implications (J Clin Psychopharmacol, 1988)</em> [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/2906070″ title=”MEDLINE”>MEDLINE</a>]: patients should be thoroughly informed of tardive dyskinesia as a potential outcome and instructed to maintain appropriate clinical monitoring</li>

</ul>

</li>

</ul>

<hr />

<h2>References</h2>

<h3>General</h3>

<h4>Miscellaneous</h4>

<ul>

<li>History and definition of tardive dyskinesia. Clin Neuropharmacol. 1983;6(2):91 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/6133621″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Malpractice and tardive dyskinesia: a conceptual dilemma. J Clin Psychopharmacol. 1988;8(4 Suppl):71S [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/2906070″ title=”MEDLINE”>MEDLINE</a>]</li>

</ul>

<h4>Antipsychotics</h4>

<ul>

<li>Behavioural supersensitivity to apomorphine following chronic treatment with drugs which interfere with the synaptic function of catecholamines. Neuropharmacology. 1974;13(10-11):927 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/4474641″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Binding of 3H-neuroleptics and 3H-apomorphine in schizophrenic brains. Nature. 1978;274(5674):897 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/683328″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Tardive dyskinesia: prevalence and risk factors, 1959 to 1979. Arch Gen Psychiatry. 1982;39(4):473 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/6121548″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>A prospective study of tardive dyskinesia development: preliminary results. J Clin Psychopharmacol. 1982;2(5):345 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/6127353″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Tardive dyskinesia. Annu Rev Med. 1984;35:605 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/6144288″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Integrating incidence and prevalence of tardive dyskinesia. Psychopharmacol Bull. 1986;22(1):254 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/2873613″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Review of incidence studies of tardive dyskinesia associated with typical antipsychotics. J Clin Psychiatry. 2000;61 Suppl 4:15 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/10739326″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet. 2003;361(9369):1581 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/12747876″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>CATIE Trial. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209. Epub 2005 Sep 19 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/16172203″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Modern antipsychotic drugs: a critical overview. CMAJ. 2005;172(13):1703 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/15967975″ title=”MEDLINE”>MEDLINE</a>]</li>

</ul>

<h4>Metoclopramide (Reglan) (see <a href=”http://mdnxs.com/topics-2/pharmacology/metoclopramide/” title=”Metoclopramide”>Metoclopramide</a>, <a href=’/Metoclopramide’ class=’wiki-link ‘>Metoclopramide</a>)</h4>

<ul>

<li>Metoclopramide-induced movement disorders. Clinical findings with a review of the literature. Arch Intern Med. 1989;149(11):2486 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/2684075″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders. Arch Intern Med. 1993;153(12):1469 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/8512437″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Metoclopramide and tardive dyskinesia. Biol Psychiatry. 1994;36(9):630 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/7833431″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Drug Insight: from disturbed motility to disordered movement&ndash;a review of the clinical benefits and medicolegal risks of metoclopramide. Nat Clin Pract Gastroenterol Hepatol. 2006;3(3):138 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/16511548″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Metoclopramide, an increasingly recognized cause of tardive dyskinesia. J Clin Pharmacol. 2008;48(3):379. Epub 2008 Jan 25 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/18223146″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Review article: metoclopramide and tardive dyskinesia. Aliment Pharmacol Ther. 2010 Jan;31(1):11-9. doi: 10.1111/j.1365-2036.2009.04189.x [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/19886950″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>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 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/22875741″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Metoclopramide-induced tardive respiratory dyskinesia. J Neuropsychiatry Clin Neurosci. 2012 Summer;24(3):E37-8. doi: 10.1176/appi.neuropsych.11070174 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/23037676″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>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 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/23735907″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>FDA Package Insert [<a href=”https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017854s062lbl.pdf” title=”MEDLINE”>MEDLINE</a>]</li>

</ul>

<h3>Clinical</h3>

<ul>

<li>Respiratory dysrhythmias in patients with tardive dyskinesia. Chest. 1994 Jan;105(1):203-7 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/7903923″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Neuroleptic-induced respiratory dyskinesia. J Neuropsychiatry Clin Neurosci. 1995 Spring;7(2):223-9 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/7626967″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Prevalence of and risk factors for respiratory dyskinesia. Clin Neuropharmacol. 1996 Oct;19(5):390-8 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/Prevalence of and risk factors for respiratory dyskinesia.” title=”MEDLINE”>MEDLINE</a>]</li>

<li>Multiple rib fractures secondary to severe tardive dystonia and respiratory dyskinesia. J Clin Psychiatry. 2000 Mar;61(3):215-6 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/10817109″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Respiratory dyskinesia&ndash;an under-recognized side-effect of neuroleptic medications. Pak Med Assoc. 2011 Sep;61(9):930-2 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/22360044″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Metoclopramide-induced tardive respiratory dyskinesia. J Neuropsychiatry Clin Neurosci. 2012 Summer;24(3):E37-8. doi: 10.1176/appi.neuropsych.11070174 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/23037676″ title=”MEDLINE”>MEDLINE</a>]</li>

<li>Tardive tachypnea. Intensive Care Med. 2016 Dec;42(12):2126. doi: 10.1007/s00134-016-4555-5. Epub 2016 Oct 3 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/27699455″ title=”MEDLINE”>MEDLINE</a>]</li>

</ul>

<h3>Prevention</h3>

<ul>

<li>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 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/6106389″ title=”MEDLINE”>MEDLINE</a>]</li>

</ul>

<h3>Treatment</h3>

<ul>

<li>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 [<a href=”http://www.ncbi.nlm.nih.gov/pubmed/28320223″ title=”MEDLINE”>MEDLINE</a>]</li>

</