01Approach to the Critical Patient/attcp34

Airway and breathing

›Respiratory dyskinesia — rare but life-threatening

›Diaphragmatic or pharyngeal involvement causing irregular breathing pattern

›SpO2 monitoring for hypoxia

›If airway compromise, immediate anesthesia or critical care consult

›Supplemental oxygen for SpO2 < 94%

›Dysphagia assessment

›Severe orofacial dyskinesia impairing swallowing

›Aspiration risk from impaired pharyngeal mechanics

›NPO status if unable to protect airway or maintain oral intake

›Speech-language pathology consult for swallowing evaluation

Immediate stabilization

›NMS exclusion — highest priority

›Hyperthermia (temperature > 38.5 C)

›Severe muscle rigidity

›Altered mental status

›Autonomic instability (labile BP, tachycardia, diaphoresis)

›Elevated CK if NMS suspected

›If NMS present, discontinue DRBA immediately and initiate NMS protocol

›Hemodynamic monitoring

›Continuous cardiac monitoring for QT prolongation risk

›IV access in critically ill patients

›CBC, CMP, and CK if systemic illness suspected

Key decision points

›Critical treatment reversal rule

›Anticholinergics (benztropine, diphenhydramine) worsen TD — NEVER give for TD

›Anticholinergics treat acute dystonia and drug-induced parkinsonism — opposite of TD

›Antipsychotic dose increase transiently masks TD but worsens long-term prognosis

02History/hx52

Medication exposure

›Dopamine receptor blocking agent (DRBA) exposure

›First-generation antipsychotics: haloperidol, chlorpromazine, fluphenazine — highest risk

›Second-generation antipsychotics: risperidone, olanzapine, quetiapine, aripiprazole — lower but significant risk

›Antiemetics: metoclopramide, prochlorperazine, promethazine

›Duration of exposure: minimum 3 months (minimum 1 month if age >= 60)

›Long-acting injectable antipsychotics — onset of TD may occur within 8 weeks of discontinuation

›Recent medication changes

›Dose reduction or discontinuation of antipsychotic can transiently worsen involuntary movements

›Addition of anticholinergic agents worsens TD

›Stimulant or substance use worsening movements

Symptom characterization

›Onset and timing

›Insidious onset during DRBA treatment or within 4 weeks of oral DRBA discontinuation

›Onset within 8 weeks of long-acting injectable discontinuation

›Gradual progression over months — distinguishes from acute dystonia (hours) and akathisia (days-weeks)

›Movement characteristics

›Orofacial: lip smacking, tongue protrusion, chewing, grimacing

›Limb: repetitive finger/toe movements, piano-playing movements

›Truncal: rocking, twisting, pelvic thrusting

›Movements are involuntary and stereotyped (repetitive pattern)

›Absent during sleep

›Worsened by stress, stimulants, anticholinergic medications

›Transiently suppressed by voluntary movement of affected body part

Alarm features

›Life-threatening presentations

›Respiratory dyskinesia: diaphragmatic or pharyngeal involvement, irregular breathing

›Severe dysphagia: aspiration risk, inability to maintain oral intake, weight loss

03Physical Exam/exam46

Movement disorder assessment

›Orofacial dyskinesia

›Lip smacking or pursing

›Tongue protrusion or writhing

›Repetitive chewing or jaw movements

›Grimacing, blepharospasm

›Perioral and facial choreiform movements

›Limb and truncal movements

›Repetitive finger or hand movements (piano-playing)

›Foot or toe tapping

›Trunk rocking, pelvic thrusting

›Choreiform limb movements

AIMS-guided examination

›Abnormal Involuntary Movement Scale domains

›Facial and oral movements: muscles of facial expression, lips, perioral area

›Extremity movements: upper and lower limbs

›Trunk movements: neck, shoulders, hips

›Global severity rating: none (0), minimal (1), mild (2), moderate (3), severe (4)

›Dental status (ill-fitting dentures can mimic orofacial TD)

›Global incapacitation score

›Patient awareness and distress rating

Neurological exam

›Motor system

›Tone: hypotonia typical in TD (vs. rigidity in drug-induced parkinsonism or NMS)

›Bradykinesia: presence suggests drug-induced parkinsonism overlay

›Resting tremor: 3-6 Hz suggests drug-induced parkinsonism rather than TD

›Postural stability and gait

›Cognitive and mental status

04Differential Diagnosis/ddx48

Drug-induced movement disorders

›Drug-induced parkinsonism (ICD-10: G21.11)

›Hypokinetic: bradykinesia, rigidity, resting tremor 3-6 Hz

›Onset within days-weeks of DRBA initiation or dose increase

›Treatment: reduce or switch DRBA; anticholinergics may help — OPPOSITE of TD

›Acute dystonia (ICD-10: G24.02)

›Sustained involuntary muscle contractions causing abnormal postures

›Onset within hours to days of DRBA initiation — much more acute than TD

›Treatment: diphenhydramine 50 mg IV or benztropine 1-2 mg IV

›Akathisia (ICD-10: G21.11)

›Subjective inner restlessness with inability to remain still

›Pacing, rocking, leg crossing — no orofacial stereotypy

›Onset within days to weeks of DRBA initiation or dose increase

›Withdrawal dyskinesia

›Emerges within days of DRBA dose reduction or discontinuation

›If persists > 4 weeks after discontinuation of oral agent, meets criteria for TD

›Typically resolves within 4-8 weeks

Tardive dyskinesia (ICD-10: G24.01)

›DSM-5 diagnostic criteria

›Involuntary athetoid or choreiform movements of face, tongue, or extremities

›Developed after >= 3 months of DRBA exposure (>= 1 month if age >= 60)

›Not better explained by a neurological or medical condition

›Movements persist for > 4 weeks after last DRBA exposure or dose change

Neurological mimics

›Huntington disease (ICD-10: G10)

›Progressive chorea plus cognitive decline and psychiatric symptoms

›Autosomal dominant family history

›Genetic testing: CAG repeat expansion in HTT gene

05Laboratory Tests/lt41

Basic metabolic workup

›Comprehensive metabolic panel

›Hepatic function: elevated bilirubin, transaminases in Wilson disease or hepatic impairment

›Hepatic impairment affects VMAT2 inhibitor dosing — critical prior to treatment

›Electrolytes and glucose: metabolic contributors to movement disorder

›Complete blood count

›Leukocytosis if NMS or aspiration pneumonia complicating course

›Baseline prior to VMAT2 inhibitor initiation

›Creatine kinase

›Markedly elevated (> 1000 U/L) in NMS

›Mild elevation possible in severe TD with muscular hyperactivity

›Critical NMS exclusion test

Thyroid and metabolic screen

›Thyroid-stimulating hormone

›Thyrotoxicosis as a mimic (TSH suppressed)

›Hypothyroidism can exacerbate movement disorders

›Ceruloplasmin

›< 0.2 g/L supports Wilson disease diagnosis in young patients

›Indicated when age < 40 or hepatic disease present

›24-hour urine copper

›> 1.6 micromol/day (100 microg/day) supports Wilson disease

›Indicated in Wilson disease workup

Genetic and specialized testing

›Huntington gene testing

›CAG repeat expansion in HTT gene

›Indicated when family history or progressive cognitive decline present

›Requires genetic counselling pre-testing

›Antinuclear antibody and anti-dsDNA

06Diagnostic Tests/dt51

Scoring Systems

›Abnormal Involuntary Movement Scale (AIMS)

›Gold standard clinical rating scale for TD severity

›12-item scale: 7 movement items (0-4 each), 2 global items, dental status, awareness

›Total movement score 0-28; higher score = greater severity

›AIMS total score used to monitor treatment response at each visit

›Clinically meaningful improvement: >= 30% reduction from baseline AIMS score

›Validated tool for both diagnosis and treatment monitoring

›DSM-5 Diagnostic Criteria for Tardive Dyskinesia

›Criterion A: involuntary athetoid or choreiform movements

›Criterion B: >= 3 months DRBA exposure (>= 1 month if age >= 60)

›Criterion C: not explained by another neurological condition

›Criterion D: not purely withdrawal dyskinesia (symptoms > 4 weeks after DRBA change)

›Extrapyramidal Symptom Rating Scale (ESRS)

›Broader scale rating parkinsonism, dystonia, akathisia, and TD

›Useful when multiple drug-induced movement disorders overlap

›Subscale scoring allows delineation of TD from co-occurring EPS

MRI

›Brain MRI indications

›Not routinely required for typical TD presentation with clear DRBA exposure history

›Indicated when diagnostic uncertainty exists or atypical features present

›Indications include: new focal neurological signs, progressive cognitive decline, young age without DRBA history, family history of hereditary chorea

›MRI findings in TD mimics

›Huntington disease: caudate nucleus atrophy on T1 imaging; MRI sensitivity ~70% in early disease

›Wilson disease: T2 hyperintensity in basal ganglia, thalamus, brainstem ("face of the giant panda" sign)

›Stroke-related chorea: DWI/FLAIR hyperintensity in contralateral subthalamic nucleus or striatum

›TD itself: no pathognomonic MRI findings; diagnosis is clinical

›Protocol guidance

07Disposition/dispo25

Admission indications

›Emergent admission criteria

›Respiratory dyskinesia with airway compromise or hypoxia

›Severe dysphagia with aspiration risk or inability to maintain oral intake

›Suicidal ideation or active psychiatric decompensation

›Confirmed or suspected NMS (fever, rigidity, altered mental status, autonomic instability)

›Significant weight loss or malnutrition from impaired eating mechanics

›Oral trauma requiring urgent intervention

›Psychiatric admission criteria

›Acute psychiatric instability requiring medication adjustment in monitored setting

›Inability to maintain safety or medication adherence as outpatient

Discharge criteria

›Safe discharge requirements

›Mild-to-moderate TD without airway, swallowing, or safety concerns

›Hemodynamically stable and tolerating oral intake

›NMS excluded clinically or by investigation

›Appropriate psychiatric follow-up arranged within 1-2 weeks

›Patient and caregiver education on return precautions completed

›Unsafe medications identified and discontinued or flagged

Consult requirements

›Mandatory consults

›Psychiatry: all confirmed TD cases for medication review and VMAT2 inhibitor consideration

›Neurology/movement disorders: diagnostic uncertainty, severe or refractory TD, botulinum toxin or DBS consideration

›Speech-language pathology: significant orofacial involvement with dysphagia

›Follow-up planning

›Psychiatry within 1-2 weeks for medication adjustment and VMAT2 inhibitor titration

›Serial AIMS assessment at baseline and every follow-up visit to track treatment response

›If VMAT2 inhibitor initiated: reassessment at 2-4 weeks for dose titration and side effect review

08Treatment/t71

Immediate management

›Stop or minimize the offending agent

›Reduce or discontinue causative DRBA where clinically safe

›Abrupt discontinuation of antipsychotic may precipitate psychiatric relapse — taper with psychiatry guidance

›Switch to lower-risk antipsychotic (clozapine or quetiapine) when antipsychotic cannot be discontinued

›Clozapine: very low TD risk; consider when ongoing antipsychotic therapy required

›Quetiapine: lower TD risk among SGAs; acceptable alternative

›Medications to avoid

›Anticholinergics (benztropine, trihexyphenidyl, diphenhydramine) — worsen TD

›Antipsychotic dose increase — transiently masks symptoms but worsens long-term prognosis

›Stimulants and cocaine — exacerbate dyskinesia

VMAT2 inhibitors — first-line treatment

›Valbenazine (Ingrezza) — FDA-approved 2017

›Starting dose: 40 mg PO once daily for 1 week

›Maintenance dose: 80 mg PO once daily after week 1

›Dose reduction to 40 mg daily for: hepatic impairment (Child-Pugh B or C), CYP2D6 poor metabolizers, CYP3A4 inhibitor co-administration

›Maximum dose: 80 mg daily

›Can be taken with or without food

›Avoid strong CYP3A4 inducers (rifampin, carbamazepine) — reduces valbenazine exposure

›Class I recommendation; NNT approximately 5 for clinically meaningful improvement

›Deutetrabenazine (Austedo) — FDA-approved 2017

›Starting dose: 6 mg PO twice daily with food

›Titration: increase by 6 mg/day at weekly intervals

›Maximum dose: 24 mg twice daily (48 mg/day total)

›Reduce dose in CYP2D6 poor metabolizers: maximum 36 mg/day

›Must be taken with food — bioavailability reduced 50% without food

›Contraindicated in hepatic impairment (Child-Pugh B or C)

›Class I recommendation

VMAT2 inhibitor safety monitoring

›Cardiac monitoring

›QTc prolongation risk with both VMAT2 inhibitors

›Baseline ECG prior to initiation

›Avoid in congenital long QT syndrome

›Avoid co-administration with other QT-prolonging agents

›Psychiatric monitoring

›Both agents carry warnings for depression and suicidality

›Baseline depression screen (PHQ-9 or equivalent)

›Monitor for worsening depression or suicidal ideation during titration

›Contraindicated with MAO inhibitors (hypertensive crisis risk for deutetrabenazine)

›Efficacy monitoring

›AIMS reassessment at 2-4 weeks after dose change

›Clinically meaningful improvement: >= 30% reduction in AIMS total score

›Consider dose increase if insufficient response after 4-6 weeks at maintenance dose

Adjunctive pharmacotherapy

›Clonazepam

›Probable efficacy for short-term symptomatic relief (AAN Level B evidence)

›Starting dose: 0.5 mg PO twice daily

›Titration: increase by 0.5 mg every 3-7 days as tolerated

›Maximum dose: 4-6 mg/day

›Caution: tolerance develops; efficacy wanes after 3-5 months

›Caution: sedation, falls risk, dependence — especially in elderly

›Amantadine

›Level C evidence (AAN 2013 guideline)

›Dose: 100 mg PO twice daily; maximum 300 mg/day

›Mechanism: NMDA antagonism and dopaminergic effects

›Reduce dose in renal impairment

›Ginkgo biloba extract

›Level B evidence (AAN guideline) for probable efficacy

›Dose: 240 mg/day standardized extract

›Antioxidant mechanism — may reduce oxidative stress-mediated dopaminergic damage

›Tetrabenazine

›Level C evidence; predates FDA approval of deutetrabenazine

›Dose: start 12.5 mg daily, titrate to maximum 25 mg three times daily

›Shorter half-life than deutetrabenazine; more frequent dosing required

›Higher risk of depression and parkinsonism than deutetrabenazine

Focal tardive dystonia treatment

›Botulinum toxin injection

›Indicated for focal tardive dystonia (sustained posturing of specific muscle groups)

›Most effective for cervical dystonia, blepharospasm, oromandibular dystonia

›Duration of effect: 3-4 months; repeat injections required

›Neurology or movement disorders administration

›Deep brain stimulation

›Reserved for severe, refractory TD unresponsive to pharmacotherapy

›Globus pallidus internus (GPi) target for TD

›Case series and small trials show significant benefit in selected patients

›Neurosurgery and movement disorders team evaluation required

09Special Populations/sp48

Pregnancy

›DRBA exposure in pregnancy

›Antipsychotics generally continued in pregnancy when benefits outweigh risks

›Neonatal extrapyramidal symptoms and withdrawal reported with third-trimester antipsychotic exposure

›Metoclopramide use in pregnancy: considered relatively safe but avoid prolonged use (> 12 weeks) given TD risk

›VMAT2 inhibitor safety

›Valbenazine: pregnancy Category not assigned under new FDA labeling; limited human data; animal studies show fetal harm at high doses

›Deutetrabenazine: limited human pregnancy data; use only if clearly needed

›Generally avoid initiating VMAT2 inhibitors during pregnancy; defer to postpartum

›Breastfeeding: both valbenazine and deutetrabenazine excreted in breast milk in animal models; avoid breastfeeding during treatment

›Management approach in pregnancy

›Multidisciplinary team: psychiatry, maternal-fetal medicine, neurology

›Consider lowest-risk antipsychotic switch if ongoing therapy required

›Clonazepam: associated with neonatal benzodiazepine withdrawal; use with caution; avoid in first trimester (cleft palate risk uncertain)

›Non-pharmacological interventions preferred where possible

Geriatric

›Increased risk and severity

›Age > 55: TD incidence up to 25-30% after 1 year of DRBA exposure

›Postmenopausal women at highest risk among elderly

›Reduced dopaminergic reserve with aging increases vulnerability

›TD may be partially irreversible even after DRBA discontinuation in elderly

›VMAT2 inhibitor dosing in elderly

›Valbenazine: no dose adjustment required for age alone; monitor for falls and sedation

›Deutetrabenazine: use lowest effective dose; increased fall risk with sedation

›QTc prolongation risk increases with age — ECG monitoring essential

›Comorbidity management

›Anticholinergics (on Beers Criteria 2023) worsens TD and causes cognitive impairment in elderly — avoid

›Clonazepam: high fall and sedation risk in elderly — use with caution or avoid

10Background/b53

Epidemiology

›Prevalence

›Overall TD prevalence in patients exposed to antipsychotics: 20-30% (first-generation), 13% (second-generation)

›Annualized incidence: approximately 5.5% per year with first-generation antipsychotics; 3.9% per year with second-generation antipsychotics

›Estimated 500,000 people with TD in the United States

›TD associated with significant morbidity: social isolation, depression, suicidality, functional impairment

›Demographics

›Age: incidence increases markedly after age 55; rate up to 25-30% after 1 year in elderly

›Sex: postmenopausal women have higher risk; possibly estrogen-related neuroprotection prior to menopause

›Psychiatric diagnoses most commonly treated with DRBAs: schizophrenia, bipolar disorder, MDD, schizoaffective disorder

›Non-psychiatric indications for DRBAs: nausea and vomiting (metoclopramide most common offending antiemetic)

›Causative agents

›First-generation antipsychotics (haloperidol, chlorpromazine, fluphenazine): highest TD risk

›Second-generation antipsychotics (risperidone, olanzapine, aripiprazole): lower but clinically significant TD risk

›Antiemetics: metoclopramide and prochlorperazine; often underrecognized as DRBA

›Duration for risk: minimum 3 months of exposure; risk increases with cumulative dose and duration

Pathophysiology

›Dopamine receptor supersensitivity hypothesis

›Chronic D2 receptor blockade leads to upregulation and supersensitivity of postsynaptic D2 receptors in striatum

›Periodic or intermittent dopaminergic stimulation of supersensitive receptors produces involuntary movements

›Explains why dose reduction or DRBA discontinuation can transiently worsen TD

›Explains why increasing antipsychotic dose temporarily suppresses movements (then worsens sensitivity)

›Oxidative stress mechanism

›Dopamine metabolism generates reactive oxygen species

›Chronic dopaminergic dysregulation leads to oxidative damage to striatal neurons

›Basal ganglia (striatum, putamen, caudate) are primary affected structures

›Ginkgo biloba antioxidant mechanism targets this pathway (Level B evidence)

›Synaptic plasticity and GABAergic dysfunction

›Striatal GABAergic interneuron dysfunction contributes to loss of movement inhibition

›Imbalance between direct pathway (movement facilitation) and indirect pathway (movement suppression)

›NMDA receptor-mediated excitotoxicity may contribute — basis for amantadine therapy

›VMAT2 mechanism

›Vesicular monoamine transporter 2 (VMAT2) packages dopamine into synaptic vesicles

›VMAT2 inhibition reduces dopaminergic neurotransmission at striatal synapses

›Reduces excessive dopaminergic activation of supersensitive D2 receptors

›Mechanism of action of valbenazine and deutetrabenazine

Therapeutic Considerations

›Natural history and reversibility

›TD may be partially or fully irreversible, especially after prolonged DRBA exposure

›Early intervention (within first few months of TD onset) associated with better reversibility

›Up to 50% of patients show improvement after DRBA discontinuation; 20-40% achieve remission over years

›Elderly patients have lower rates of spontaneous remission

›Treatment goals

›Reduction in AIMS score as primary endpoint (>= 30% reduction is clinically meaningful)

›Improvement in functional capacity: eating, speaking, social interaction

›Reduction in psychiatric comorbidity (depression, suicidality) associated with TD

›VMAT2 inhibitor comparative pharmacology

›Valbenazine: selective VMAT2 inhibitor; once-daily dosing; CYP3A4/CYP2D6 metabolism

›Deutetrabenazine: deuterium-modified tetrabenazine; twice-daily dosing; more stable plasma levels than tetrabenazine; CYP2D6 metabolism

›Both FDA-approved; network meta-analysis (Solmi 2025) supports both as most effective pharmacological options

›Head-to-head trials limited; choice based on dosing preference, comorbidities, drug interactions

›Evidence base

›AAN 2013 guideline: clonazepam (Level B), ginkgo biloba (Level B), amantadine (Level C), tetrabenazine (Level C)

›FDA approval of valbenazine 2017 and deutetrabenazine 2017 based on Phase 3 randomized controlled trials

›Canadian Journal of Psychiatry 2019 treatment recommendations support VMAT2 inhibitors as first-line

›Bhidayasiri et al. 2018 updated algorithm recommends reducing/stopping DRBA first, then VMAT2 inhibitors

11Patient Discharge Instructions/pdi28

copy discharge instructions

›What is tardive dyskinesia?

›TD is a movement disorder caused by medications that block dopamine receptors in the brain

›Common causative medications include antipsychotics (for mental health conditions) and some anti-nausea medications such as metoclopramide

›Symptoms include uncontrolled movements of the face, tongue, lips, hands, or body

›TD can be a permanent condition but treatment can reduce symptoms significantly

›Your medications

›Do not stop or change your psychiatric medications without speaking to your psychiatrist first — abrupt stopping can cause serious psychiatric relapse

›Avoid all anticholinergic medications — these can worsen your involuntary movements

›Common anticholinergics to avoid: benztropine (Cogentin), diphenhydramine (Benadryl), trihexyphenidyl

›If started on valbenazine (Ingrezza): take once daily; can be taken with or without food

›If started on deutetrabenazine (Austedo): take twice daily with food — food is required for proper absorption

›Both medications work slowly — improvement may take several weeks

›Follow-up instructions

›Follow up with your psychiatrist within 1-2 weeks for medication review and treatment adjustment

›Neurologist or movement disorder specialist referral may be arranged for further evaluation

›Bring a list of all your current medications to every appointment

›Serial movement assessments (AIMS scale) will be performed at follow-up visits to track your progress

›Diet and daily life

›If you have difficulty chewing or swallowing, eat soft foods and take small bites

›Avoid stimulants including caffeine and recreational drugs — these can worsen movements

›Report any difficulty breathing, swallowing, or eating to your doctor immediately

›Return to emergency department immediately for

›Difficulty breathing or irregular breathing pattern

›Inability to eat, drink, or swallow safely

›High fever, severe muscle stiffness, or confusion — these may indicate a serious drug reaction

›Worsening involuntary movements

›New or worsening thoughts of self-harm or suicide

12References/r40

Guidelines and key sources

›American Psychiatric Association DSM-5-TR (2022)

›Diagnostic criteria for tardive dyskinesia

›Duration criteria: >= 3 months DRBA exposure (>= 1 month if age >= 60)

›AAN Evidence-Based Guideline: Treatment of Tardive Syndromes (Bhidayasiri et al., Neurology 2013)

›Clonazepam: Level B (probably effective)

›Ginkgo biloba 240 mg/day: Level B (probably effective)

›Amantadine and tetrabenazine: Level C (possibly effective)

›Bhidayasiri et al. Journal of Neurological Sciences 2018

›Updated treatment algorithm; systematic review of new evidence

›VMAT2 inhibitors added as preferred first-line treatment

›FDA Drug Label: Valbenazine (Ingrezza) — Updated 2026

›40 mg daily for 1 week, then 80 mg daily

›Dose adjustment for hepatic impairment and CYP2D6 poor metabolizers

›Ricciardi L et al. Canadian Journal of Psychiatry 2019

›Treatment recommendations for tardive dyskinesia

›VMAT2 inhibitors as first-line pharmacotherapy

›Factor SA et al. Lancet Neurology 2019

›Recent developments in drug-induced movement disorders

›Distinguishing features of TD, acute dystonia, akathisia, drug-induced parkinsonism

Key clinical evidence

›Marder SR, Cannon TD. NEJM 2019

›Annualized TD incidence: 5.5% per year first-generation antipsychotics; 3.9% second-generation

›TD prevalence: 32% first-generation vs 13% second-generation antipsychotics

›Correll CU, Citrome L. Journal of Clinical Psychiatry 2021

›Diagnostic and treatment fundamentals for tardive dyskinesia

›Serial AIMS assessment recommended at baseline and each follow-up visit

›Solmi M et al. Molecular Psychiatry 2025

Evidence & Review

Evidence & Review