Drug-Induced Parkinsonism¶
VERSION: 1.1 CREATED: January 30, 2026 REVISED: January 30, 2026 STATUS: Approved
DIAGNOSIS: Drug-Induced Parkinsonism (DIP)
ICD-10: G21.11 (Neuroleptic induced parkinsonism), G21.19 (Other drug induced secondary parkinsonism), G21.0 (Malignant neuroleptic syndrome); CPT: 99213-99215 (E&M outpatient), 99221-99223 (E&M inpatient), 78830 (DaTscan), 70553 (MRI brain with/without contrast)
CPT CODES: 85025 (CBC), 80053 (CMP), 84443 (TSH), 82947 (Glucose), 82390 (Serum ceruloplasmin), 82607 (Vitamin B12), 86592 (RPR/VDRL), 87389 (HIV), 82550 (CK), 84439 (Free T4), 80164 (Valproic acid level), 80178 (Lithium level), 70551 (MRI brain without contrast), 78830 (DaTscan), 70553 (MRI brain with contrast), 78608 (FDG-PET brain), 95810 (Polysomnography)
SYNONYMS: Drug-induced parkinsonism, DIP, neuroleptic-induced parkinsonism, medication-induced parkinsonism, secondary parkinsonism, antipsychotic-induced parkinsonism, drug-induced extrapyramidal symptoms, iatrogenic parkinsonism, medication-related parkinsonism, dopamine blocker parkinsonism, antidopaminergic parkinsonism, metoclopramide-induced parkinsonism, pseudoparkinsonism
SCOPE: Diagnosis and management of parkinsonism (tremor, rigidity, bradykinesia, postural instability) caused by dopamine-blocking or dopamine-depleting medications. Covers identification of causative agents, differentiation from idiopathic Parkinson's disease, medication discontinuation/substitution strategies, symptomatic treatment, and psychiatric collaboration for patients requiring continued antipsychotic therapy. Excludes idiopathic Parkinson's disease (separate protocol), vascular parkinsonism, atypical parkinsonian syndromes (PSP, MSA, CBD, DLB), neuroleptic malignant syndrome (acute management), and tardive dyskinesia (separate protocol).
DEFINITIONS: - Drug-Induced Parkinsonism (DIP): Parkinsonism caused by medications that block or deplete dopamine, typically presenting within days to months of exposure - Parkinsonism: Clinical syndrome of bradykinesia plus at least one of: rest tremor, rigidity, or postural instability - Bradykinesia: Slowness of movement with progressive reduction in speed and amplitude with repetitive actions - Rest Tremor: 4-6 Hz tremor present at rest, suppressed with action (may be less prominent in DIP than idiopathic PD) - Dopamine Receptor Blocking Agent (DRBA): Medications that antagonize D2 dopamine receptors (antipsychotics, antiemetics) - DaTscan: Dopamine transporter imaging used to differentiate DIP (normal uptake) from idiopathic PD (reduced uptake)
COMMON CAUSATIVE AGENTS:
| Drug Class | High Risk | Moderate Risk | Lower Risk |
|---|---|---|---|
| Typical antipsychotics | Haloperidol, chlorpromazine, fluphenazine, perphenazine | Loxapine, thiothixene | - |
| Atypical antipsychotics | Risperidone (dose-dependent) | Olanzapine, ziprasidone, paliperidone | Quetiapine, clozapine, aripiprazole |
| Antiemetics | Metoclopramide, prochlorperazine | Promethazine | Ondansetron (no risk) |
| Calcium channel blockers | Flunarizine, cinnarizine | - | - |
| Mood stabilizers | - | Valproate, lithium | - |
| Other | Tetrabenazine, reserpine (dopamine depletors) | Amiodarone, methyldopa | - |
KEY CLINICAL FEATURES DISTINGUISHING DIP FROM IDIOPATHIC PD:
| Feature | DIP | Idiopathic PD |
|---|---|---|
| Onset | Subacute (days to months after drug exposure) | Insidious (months to years) |
| Symmetry | Often bilateral and symmetric | Typically asymmetric, unilateral onset |
| Tremor | Less prominent; postural > rest | Rest tremor classic (4-6 Hz, pill-rolling) |
| Temporal relationship | Onset after causative medication initiation | No drug temporal relationship |
| DaTscan | Normal (presynaptic dopamine intact) | Abnormal (reduced striatal uptake) |
| Resolution | Improves within weeks to months after drug withdrawal | Progressive, no spontaneous improvement |
| Associated features | May have orobuccal dyskinesia, akathisia | Olfactory loss, REM sleep behavior disorder |
PRIORITY KEY: STAT = Immediate | URGENT = Within hours | ROUTINE = Standard | EXT = Extended/atypical cases | - = Not applicable to this setting
═══════════════════════════════════════════════════════════════ SECTION A: ACTION ITEMS ═══════════════════════════════════════════════════════════════
1. LABORATORY WORKUP¶
1A. Essential/Core Labs¶
| Test | ED | HOSP | OPD | ICU | Rationale | Target Finding |
|---|---|---|---|---|---|---|
| CBC (CPT 85025) | URGENT | ROUTINE | ROUTINE | URGENT | General health assessment; rule out infection; leukocytosis if NMS suspected | Normal |
| CMP (CPT 80053) | URGENT | ROUTINE | ROUTINE | URGENT | Hepatic/renal function for medication dosing and clearance assessment | Normal |
| TSH (CPT 84443) | ROUTINE | ROUTINE | ROUTINE | - | Hypothyroidism can cause bradykinesia and psychomotor slowing | Normal (0.4-4.0 mIU/L) |
| Medication reconciliation | STAT | STAT | ROUTINE | STAT | Identify all dopamine-blocking or depleting agents including OTC and herbal | Complete list of all current and recent medications |
| Drug levels (if applicable) | URGENT | ROUTINE | ROUTINE | URGENT | Assess toxicity or supratherapeutic levels of causative agent (valproate, lithium) | Therapeutic range |
| Glucose (CPT 82947) | URGENT | ROUTINE | ROUTINE | URGENT | Metabolic evaluation; diabetes as comorbidity | Normal |
1B. Extended Workup (Second-line)¶
| Test | ED | HOSP | OPD | ICU | Rationale | Target Finding |
|---|---|---|---|---|---|---|
| Serum ceruloplasmin (CPT 82390) | - | ROUTINE | ROUTINE | - | Wilson disease if age <50 or atypical features | 20-40 mg/dL |
| 24-hour urine copper | - | EXT | EXT | - | Wilson disease if ceruloplasmin low or borderline | <100 mcg/24h |
| Vitamin B12 (CPT 82607) | - | ROUTINE | ROUTINE | - | Deficiency can contribute to neurologic dysfunction | >400 pg/mL |
| RPR/VDRL (CPT 86592) | - | ROUTINE | ROUTINE | - | Neurosyphilis in differential for parkinsonism | Negative |
| HIV (CPT 87389) | - | ROUTINE | ROUTINE | - | HIV-associated parkinsonism | Negative |
| CK (CPT 82550) | URGENT | ROUTINE | - | URGENT | Evaluate for NMS if fever, rigidity, autonomic instability present | Normal (30-200 U/L) |
| Serum iron studies | - | ROUTINE | ROUTINE | - | Iron deposition disorders in differential | Normal |
| Free T4 (CPT 84439) | - | ROUTINE | ROUTINE | - | If TSH abnormal | Normal |
| Valproic acid level (CPT 80164) | URGENT | ROUTINE | ROUTINE | URGENT | If on valproate; supratherapeutic levels increase risk | 50-100 mcg/mL |
| Lithium level (CPT 80178) | URGENT | ROUTINE | ROUTINE | URGENT | If on lithium; toxicity can cause parkinsonism | 0.6-1.2 mEq/L |
1C. Rare/Specialized¶
| Test | ED | HOSP | OPD | ICU | Rationale | Target Finding |
|---|---|---|---|---|---|---|
| Serum/urine heavy metals | - | - | EXT | - | Manganese, lead exposure history | Normal |
| Anti-neuronal antibodies | - | - | EXT | - | Autoimmune parkinsonism (anti-IgLON5, anti-CASPR2) | Negative |
| Genetic testing (GBA, LRRK2, PRKN) | - | - | EXT | - | If DIP unmasking underlying PD suspected; family history | Informational |
| Alpha-synuclein seed amplification assay | - | - | EXT | - | Emerging biomarker to detect underlying synucleinopathy unmasked by DRBA | Pending validation |
2. DIAGNOSTIC IMAGING & STUDIES¶
2A. Essential/First-line¶
| Study | ED | HOSP | OPD | ICU | Timing | Target Finding | Contraindications |
|---|---|---|---|---|---|---|---|
| MRI brain without contrast (CPT 70551) | ROUTINE | ROUTINE | ROUTINE | - | At diagnosis | Rule out structural cause, vascular parkinsonism, basal ganglia lesions | Pacemaker, metal implants |
| Clinical examination (UPDRS motor exam) | STAT | ROUTINE | ROUTINE | - | At presentation | Document severity of parkinsonism; baseline for comparison | None |
| Medication timeline review | STAT | STAT | ROUTINE | STAT | At presentation | Establish temporal relationship between medication and symptom onset | None |
2B. Extended¶
| Study | ED | HOSP | OPD | ICU | Timing | Target Finding | Contraindications |
|---|---|---|---|---|---|---|---|
| DaTscan (CPT 78830) | - | - | ROUTINE | - | When diagnostic uncertainty between DIP and idiopathic PD | Normal striatal uptake in DIP; reduced uptake suggests underlying PD | Pregnancy, iodine allergy; discontinue medications that interfere (bupropion, modafinil, amphetamines) |
| MRI brain with contrast (CPT 70553) | - | ROUTINE | ROUTINE | - | If mass lesion or infection suspected | Rule out structural lesion affecting basal ganglia | Contrast allergy, renal impairment (eGFR <30) |
| MRI susceptibility-weighted imaging | - | ROUTINE | ROUTINE | - | If iron deposition or Wilson disease suspected | Rule out basal ganglia iron or copper deposition | Per MRI contraindications |
| Olfactory testing (UPSIT) | - | - | ROUTINE | - | Supportive assessment; impaired in PD, typically normal in DIP | Normal olfaction favors DIP over PD | Nasal obstruction |
2C. Rare/Specialized¶
| Study | ED | HOSP | OPD | ICU | Timing | Target Finding | Contraindications |
|---|---|---|---|---|---|---|---|
| FDG-PET brain (CPT 78608) | - | - | EXT | - | Atypical presentation, distinguish atypical parkinsonism | Hypometabolism pattern varies by diagnosis | Per PET contraindications |
| MIBG cardiac scintigraphy | - | - | EXT | - | Distinguish underlying PD from pure DIP | Reduced uptake in PD; normal in pure DIP | Drugs affecting cardiac norepinephrine uptake |
| Polysomnography (CPT 95810) | - | - | EXT | - | If REM sleep behavior disorder suspected (suggests underlying synucleinopathy) | RBD present suggests underlying PD unmasked by DRBA | None |
| Transcranial sonography | - | - | EXT | - | Substantia nigra hyperechogenicity assessment | Hyperechogenicity suggests underlying PD | Inadequate temporal bone window |
3. TREATMENT¶
3A. Acute/Emergent - Causative Agent Management¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Discontinue causative DRBA | - | Primary treatment; removal of offending agent | - :: - :: - :: Immediate discontinuation if not psychiatrically required; gradual taper over 1-2 weeks if on antipsychotic to avoid withdrawal psychosis | Active psychosis requiring continued antipsychotic (coordinate with psychiatry) | Psychiatric status, withdrawal symptoms, rebound psychosis | STAT | STAT | ROUTINE | STAT |
| Discontinue metoclopramide | - | GI-related DIP; replace with non-dopaminergic antiemetic | - :: - :: - :: Stop metoclopramide immediately; switch to ondansetron 4-8 mg PO/IV q8h PRN for nausea | Active gastroparesis without alternative options | Nausea control, GI motility | STAT | STAT | ROUTINE | STAT |
| Discontinue prochlorperazine | - | Antiemetic-induced DIP | - :: - :: - :: Stop prochlorperazine immediately; switch to ondansetron 4-8 mg PO/IV q8h PRN for nausea/vertigo | None | Nausea/vertigo control | STAT | STAT | ROUTINE | STAT |
| Dose reduction of causative agent | - | Partial dose reduction when full discontinuation not feasible | - :: - :: - :: Reduce causative agent to minimum effective dose if complete discontinuation not possible; reassess in 2-4 weeks | Complete discontinuation preferable when safe | Symptom improvement, psychiatric stability | URGENT | URGENT | ROUTINE | URGENT |
3B. Symptomatic Treatment¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Amantadine (Symmetrel) | PO | Symptomatic relief of DIP; enhances dopamine release and has anticholinergic properties | 100 mg :: PO :: daily :: Start 100 mg daily; may increase to 100 mg BID after 1 week; max 300 mg/day; reduce dose in renal impairment (CrCl <50: 100 mg daily; CrCl <15: contraindicated) | Severe renal impairment (CrCl <15); seizure history (relative); livedo reticularis (cosmetic); pregnancy | Renal function, hallucinations, livedo reticularis, peripheral edema, confusion in elderly | - | ROUTINE | ROUTINE | - |
| Benztropine (Cogentin) | PO | Anticholinergic for DIP; particularly useful for tremor-predominant symptoms | 0.5 mg :: PO :: daily :: Start 0.5 mg daily; titrate by 0.5 mg q5-7d; usual range 1-4 mg/day in divided doses; max 6 mg/day | Narrow-angle glaucoma; GI obstruction; urinary retention; dementia; elderly (relative - prefer amantadine) | Anticholinergic effects (dry mouth, constipation, urinary retention, confusion, blurred vision), cognitive impairment in elderly, tachycardia | URGENT | ROUTINE | ROUTINE | - |
| Benztropine (Cogentin) - acute | IM, IV | Acute anticholinergic relief for severe DIP or dystonic reaction | 1 mg :: IM :: once :: 1-2 mg IM or IV for acute relief; may repeat in 30 min; transition to oral maintenance | Narrow-angle glaucoma; GI obstruction; urinary retention; dementia | Anticholinergic effects, sedation, heart rate | STAT | URGENT | - | - |
| Trihexyphenidyl (Artane) | PO | Anticholinergic for DIP; alternative to benztropine | 1 mg :: PO :: daily :: Start 1 mg daily; increase by 2 mg q3-5d; usual range 6-10 mg/day in divided doses; max 15 mg/day | Narrow-angle glaucoma; GI obstruction; urinary retention; dementia; elderly (relative) | Anticholinergic effects (dry mouth, constipation, urinary retention, confusion), cognitive impairment, tachycardia | - | ROUTINE | ROUTINE | - |
| Diphenhydramine (Benadryl) IV/IM | IV, IM | Acute symptomatic relief of DIP in ED/inpatient; mild anticholinergic properties | 25 mg :: IV :: PRN :: 25-50 mg IV/IM for acute relief; may repeat q6-8h; max 300 mg/day | Narrow-angle glaucoma; urinary retention | Sedation, anticholinergic effects, falls in elderly | URGENT | ROUTINE | - | - |
| Diphenhydramine (Benadryl) PO | PO | Mild symptomatic relief of DIP; oral maintenance | 25 mg :: PO :: TID :: 25-50 mg PO q6-8h for ongoing symptoms; max 300 mg/day | Narrow-angle glaucoma; urinary retention | Sedation, anticholinergic effects, falls in elderly | - | ROUTINE | ROUTINE | - |
3C. Second-Line/Refractory and Psychiatric Substitution¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Quetiapine (Seroquel) | PO | Low-risk antipsychotic substitute when continued antipsychotic therapy required; low D2 receptor affinity | 25 mg :: PO :: QHS :: Start 25 mg QHS; titrate based on psychiatric response; usual range 150-800 mg/day; lowest effective dose to minimize EPS risk | QT prolongation; severe hepatic impairment; concurrent use of strong CYP3A4 inhibitors | Metabolic panel (glucose, lipids), weight, QTc, sedation, orthostatic BP | - | ROUTINE | ROUTINE | - |
| Clozapine (Clozaril) | PO | Antipsychotic with lowest EPS risk; for treatment-refractory psychosis requiring continued antipsychotic | 12.5 mg :: PO :: daily :: Start 12.5 mg daily; titrate by 25-50 mg/day q1-2wk; usual range 150-450 mg/day; max 900 mg/day; requires Clozapine REMS enrollment | Prior agranulocytosis; severe neutropenia (ANC <500); uncontrolled seizures; severe cardiac disease; ileus | REMS program required (Clozapine REMS); ANC weekly x 6 months, then biweekly x 6 months, then monthly; metabolic panel, weight, glucose, lipids; seizure risk (dose-dependent); myocarditis (first month) | - | EXT | EXT | - |
| Aripiprazole (Abilify) | PO | Partial D2 agonist with lower EPS risk as antipsychotic substitute | 2 mg :: PO :: daily :: Start 2-5 mg daily; titrate based on response; usual range 10-15 mg/day; max 30 mg/day | Hypersensitivity; caution in elderly with dementia | Metabolic panel, weight, akathisia (can paradoxically worsen), EPS monitoring | - | ROUTINE | ROUTINE | - |
| Brexpiprazole (Rexulti) | PO | Partial D2 agonist with lower EPS risk; alternative to aripiprazole | 0.5 mg :: PO :: daily :: Start 0.5 mg daily; titrate to 1-2 mg daily; max 4 mg/day | Hypersensitivity; caution in elderly with dementia | Metabolic panel, weight, EPS monitoring | - | - | ROUTINE | - |
| Pimozide dose reduction | PO | When pimozide is causative agent; slow taper required | - :: PO :: - :: Reduce by 25% q1-2 weeks; do not discontinue abruptly; coordinate with psychiatry for alternative | Active psychosis without alternative (coordinate with psychiatry) | ECG (QTc prolongation), psychiatric status | - | ROUTINE | ROUTINE | - |
| Levodopa/Carbidopa (Sinemet) | PO | Trial if DIP fails to resolve after drug withdrawal (suggests unmasked idiopathic PD) | 25/100 mg :: PO :: TID :: Start 25/100 mg TID with meals; titrate by 25/100 mg q1-2 weeks; response suggests underlying PD | Narrow-angle glaucoma; concurrent non-selective MAOIs; active psychosis (relative - may worsen) | Nausea, orthostatic hypotension, dyskinesia, hallucinations (especially if psychotic history); caution: may worsen psychosis | - | ROUTINE | ROUTINE | - |
| Ondansetron (Zofran) | IV | Non-dopaminergic antiemetic substitute for acute settings when metoclopramide or prochlorperazine is causative agent | 4 mg :: IV :: PRN :: 4-8 mg IV q8h PRN for nausea; max 24 mg/day | QT prolongation; severe hepatic impairment (max 8 mg/day) | QTc if risk factors, constipation | STAT | ROUTINE | - | STAT |
| Ondansetron (Zofran) PO | PO | Non-dopaminergic antiemetic substitute for oral maintenance when dopaminergic antiemetic is causative agent | 4 mg :: PO :: TID PRN :: 4-8 mg PO q8h PRN for nausea; max 24 mg/day | QT prolongation; severe hepatic impairment (max 8 mg/day) | QTc if risk factors, constipation | - | ROUTINE | ROUTINE | - |
| Domperidone (Motilium) | PO | Peripheral dopamine antagonist for gastroparesis; does not cross BBB significantly; substitute for metoclopramide | 10 mg :: PO :: TID :: 10 mg TID before meals; max 30 mg/day; not FDA-approved in US (available via compassionate use/international pharmacy) | QT prolongation; prolactinoma; GI bleeding or obstruction; hepatic impairment | ECG before initiation and periodically; QTc must be <450 ms; electrolytes | - | - | EXT | - |
4. OTHER RECOMMENDATIONS¶
4A. Referrals & Consults¶
| Recommendation | ED | HOSP | OPD | ICU |
|---|---|---|---|---|
| Movement disorders neurology consult for diagnostic confirmation and differentiation from idiopathic PD | URGENT | URGENT | ROUTINE | - |
| Psychiatry consult for medication substitution planning if causative agent is an antipsychotic required for active psychiatric condition | URGENT | URGENT | ROUTINE | URGENT |
| Pharmacy consult for comprehensive medication reconciliation to identify all potential dopamine-blocking agents including OTC medications | ROUTINE | ROUTINE | ROUTINE | ROUTINE |
| Physical therapy for gait training, balance assessment, and fall prevention given parkinsonian motor impairment | - | ROUTINE | ROUTINE | - |
| Occupational therapy for ADL adaptation and fine motor strategies given bradykinesia and rigidity | - | ROUTINE | ROUTINE | - |
| Speech therapy for swallow evaluation if bulbar symptoms present (hypophonia, dysphagia) | - | ROUTINE | ROUTINE | - |
| Primary care follow-up for medication management and ongoing monitoring within 2-4 weeks of discharge | - | ROUTINE | ROUTINE | - |
| Gastroenterology consult if gastroparesis requires ongoing prokinetic therapy to discuss non-dopaminergic alternatives | - | ROUTINE | ROUTINE | - |
4B. Patient Instructions¶
| Recommendation | ED | HOSP | OPD |
|---|---|---|---|
| Do not restart the discontinued medication without neurology approval as this will likely cause parkinsonism recurrence | STAT | STAT | ROUTINE |
| Return immediately if new-onset high fever, severe rigidity, altered consciousness, or autonomic instability develops (may indicate neuroleptic malignant syndrome) | STAT | STAT | ROUTINE |
| Report any new tremor, stiffness, slowness, or balance problems that develop after starting any new medication to your physician promptly | ROUTINE | ROUTINE | ROUTINE |
| Symptoms may take weeks to months to fully resolve after stopping the causative medication; improvement is expected but gradual | - | ROUTINE | ROUTINE |
| Do not take over-the-counter antiemetics containing metoclopramide, prochlorperazine, or promethazine without physician approval as these can cause parkinsonism | ROUTINE | ROUTINE | ROUTINE |
| Inform all healthcare providers of your history of drug-induced parkinsonism so dopamine-blocking agents are avoided in the future | ROUTINE | ROUTINE | ROUTINE |
| Use fall precautions including assistive devices, non-slip footwear, and removal of home hazards due to balance and gait impairment | - | ROUTINE | ROUTINE |
| If parkinsonian symptoms do not improve within 3-6 months of drug withdrawal, return for re-evaluation as this may indicate underlying Parkinson's disease | - | - | ROUTINE |
4C. Lifestyle & Prevention¶
| Recommendation | ED | HOSP | OPD |
|---|---|---|---|
| Fall prevention measures including grab bars, non-slip mats, adequate lighting, and removal of loose rugs due to postural instability and gait impairment | - | ROUTINE | ROUTINE |
| Regular low-impact exercise (walking, tai chi, swimming) to maintain mobility and reduce stiffness from parkinsonian rigidity | - | ROUTINE | ROUTINE |
| Maintain medication allergy/adverse reaction list updated with all dopamine-blocking agents that caused parkinsonism for future reference | ROUTINE | ROUTINE | ROUTINE |
| Avoid alcohol which may exacerbate balance problems and interact with medications used for symptom management | - | ROUTINE | ROUTINE |
| Adequate nutrition and hydration to support neurologic recovery and prevent orthostatic hypotension | - | ROUTINE | ROUTINE |
| Home safety evaluation by occupational therapy to identify environmental hazards and recommend adaptive equipment | - | ROUTINE | ROUTINE |
| MedAlert bracelet or wallet card noting drug-induced parkinsonism and specific agents to avoid for emergency situations | - | - | ROUTINE |
═══════════════════════════════════════════════════════════════ SECTION B: REFERENCE (Expand as Needed) ═══════════════════════════════════════════════════════════════
5. DIFFERENTIAL DIAGNOSIS¶
| Alternative Diagnosis | Key Distinguishing Features | Tests to Differentiate |
|---|---|---|
| Idiopathic Parkinson's disease | Asymmetric onset; rest tremor predominant; insidious progression over months-years; olfactory loss; REM sleep behavior disorder; no temporal medication relationship | DaTscan (abnormal in PD, normal in pure DIP); olfactory testing (impaired in PD); clinical follow-up after drug withdrawal |
| Vascular parkinsonism | Lower body predominant; gait apraxia; stepwise progression; white matter disease on MRI; vascular risk factors | MRI brain (confluent white matter disease, lacunar infarcts in basal ganglia); vascular risk factor assessment |
| Progressive supranuclear palsy (PSP) | Vertical supranuclear gaze palsy; early falls (backward); axial rigidity > limb rigidity; poor levodopa response | MRI (midbrain atrophy, "hummingbird sign"); clinical features; poor medication response |
| Multiple system atrophy (MSA) | Prominent autonomic failure (orthostatic hypotension, urinary retention); cerebellar ataxia; poor levodopa response | MRI (cerebellar/pontine atrophy, "hot cross bun sign"); autonomic testing; poor medication response |
| Corticobasal degeneration (CBD) | Asymmetric limb apraxia; alien limb phenomenon; cortical sensory loss; myoclonus | MRI (asymmetric cortical atrophy); clinical features |
| Dementia with Lewy bodies (DLB) | Fluctuating cognition; visual hallucinations; parkinsonism; REM sleep behavior disorder | DaTscan (abnormal); cognitive testing; clinical criteria |
| Normal pressure hydrocephalus (NPH) | Triad: gait apraxia, urinary incontinence, dementia; magnetic gait | MRI (ventriculomegaly out of proportion to atrophy); lumbar puncture with large-volume CSF removal (gait improvement) |
| Wilson disease | Age <50; Kayser-Fleischer rings; hepatic dysfunction; psychiatric symptoms; wing-beating tremor | Ceruloplasmin (low); 24h urine copper (elevated); slit-lamp exam (K-F rings); liver function tests |
| Neuroleptic malignant syndrome (NMS) | Acute onset; high fever; severe rigidity (lead-pipe); autonomic instability; altered consciousness; elevated CK | CK (markedly elevated); WBC (leukocytosis); acute presentation; requires emergent management |
| Tardive dyskinesia (TD) | Involuntary choreiform movements (orofacial, limb, trunk); late-onset after prolonged DRBA use | AIMS examination; clinical history of prolonged DRBA exposure; distinct movement pattern from parkinsonism |
| Psychogenic (functional) parkinsonism | Variable tremor frequency; entrainment; distractibility; give-way weakness; inconsistent examination findings | Clinical examination (tremor entrainment, variability); DaTscan (normal); neuropsychiatric evaluation |
| Essential tremor | Bilateral action/postural tremor; family history; alcohol responsiveness; no bradykinesia or rigidity | DaTscan (normal in ET); clinical examination (action tremor, no parkinsonism); handwriting (large, tremulous vs micrographia) |
6. MONITORING PARAMETERS¶
| Parameter | Frequency | Target/Threshold | Action if Abnormal | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| UPDRS motor score | At diagnosis, then q2-4 weeks until resolution | Progressive improvement after drug withdrawal | If no improvement at 3-6 months, pursue DaTscan and consider underlying PD | ROUTINE | ROUTINE | ROUTINE | - |
| Psychiatric status assessment | At each visit if antipsychotic substituted or discontinued | Stable mental health without psychotic relapse | Psychiatry re-evaluation; consider alternative antipsychotic with lower EPS risk | URGENT | ROUTINE | ROUTINE | URGENT |
| Gait and balance assessment | At each visit | Improving postural stability and gait speed | Intensify physical therapy; consider assistive device; evaluate for falls | - | ROUTINE | ROUTINE | - |
| Anticholinergic side effects | At each visit if on benztropine or trihexyphenidyl | No significant cognitive impairment, urinary retention, or constipation | Reduce dose or switch to amantadine; assess cognition with MoCA if concerned | - | ROUTINE | ROUTINE | - |
| CMP/renal function | Baseline, then q3 months if on amantadine | eGFR >50 mL/min for standard amantadine dosing | Dose reduce amantadine; if CrCl <15, discontinue amantadine | - | ROUTINE | ROUTINE | - |
| ANC (if on clozapine) | Weekly x 6 months, biweekly x 6 months, then monthly | ANC >1500/mcL | If ANC 1000-1500: increase monitoring; if ANC <1000: hold clozapine and urgent hematology consult | - | ROUTINE | ROUTINE | - |
| Metabolic monitoring (if on antipsychotic substitute) | Baseline, 3 months, then annually | Normal glucose, lipids, weight | Lifestyle counseling; consider metformin; switch antipsychotic if significant metabolic effects | - | ROUTINE | ROUTINE | - |
| QTc (if on quetiapine, ondansetron, or domperidone) | Baseline, after dose changes | QTc <470 ms (women), <450 ms (men) | Dose reduce or discontinue; correct electrolytes; cardiology consult if prolonged | ROUTINE | ROUTINE | ROUTINE | - |
| Symptom resolution timeline | At each follow-up | Improvement within weeks; resolution within 3-6 months | If symptoms persist >6 months, DaTscan to evaluate for underlying PD | - | ROUTINE | ROUTINE | - |
| Fall risk assessment | At each visit | No falls; improving balance | Home safety evaluation; assistive devices; physical therapy intensification | - | ROUTINE | ROUTINE | - |
7. DISPOSITION CRITERIA¶
| Disposition | Criteria |
|---|---|
| Discharge home from ED | Mild parkinsonism; causative agent identified and discontinued/substituted; outpatient neurology follow-up arranged within 2-4 weeks; no concern for NMS; patient/family educated on medication avoidance |
| Admit to floor | Severe parkinsonism causing functional impairment (unable to ambulate safely, unable to perform ADLs); need for psychiatric medication adjustment requiring close observation; complex medication reconciliation requiring pharmacy and multidisciplinary input; concern for diagnostic uncertainty requiring inpatient workup |
| Admit to ICU | Suspected neuroleptic malignant syndrome (fever, severe rigidity, autonomic instability, altered consciousness); severe dysphagia with aspiration risk; inability to protect airway; hemodynamic instability |
| Transfer to higher level | Diagnostic uncertainty requiring movement disorders specialist not available at current facility; suspected NMS requiring critical care not available locally |
| Discharge from hospital | Parkinsonism stabilized or improving; psychiatric medications adjusted with stable mental status for 48-72 hours; safe ambulation with or without assistive device; outpatient follow-up arranged with neurology and psychiatry; patient/family educated on medication avoidance |
8. EVIDENCE & REFERENCES¶
| Recommendation | Evidence Level | Source |
|---|---|---|
| DIP is the second most common cause of parkinsonism after idiopathic PD; occurs in 20-40% of patients on DRBAs | Class II, Level B | Shin HW, Chung SJ. J Clin Neurol 2012 PubMed: 22787491 |
| Symmetric parkinsonism and absence of rest tremor favor DIP over idiopathic PD | Class II, Level B | Lopez-Sendon J et al. Expert Rev Neurother 2012 PubMed: 23002938 |
| DaTscan (ioflupane I-123) effectively differentiates DIP from idiopathic PD with high sensitivity and specificity | Class I, Level A | Brigo F et al. Parkinsonism Relat Disord 2014 PubMed: 25258329 |
| Metoclopramide is the most common non-antipsychotic cause of DIP; FDA black box warning for prolonged use | Class II, Level B | Avorn J et al. Ann Intern Med 1995 PubMed: 7872590 |
| Symptoms typically resolve within weeks to months after discontinuation of the causative agent | Class II, Level B | Brigo F et al. J Neurol Sci 2014 PubMed: 25108809 |
| Approximately 10-15% of DIP patients have persistent parkinsonism after drug withdrawal suggesting unmasked underlying PD | Class II, Level B | Burn DJ, Brooks DJ. Brain 1993 PubMed: 8461577 |
| DaTscan is normal in pure DIP but abnormal in patients with DIP unmasking subclinical PD | Class I, Level A | Tinazzi M et al. Neurology 2009 PubMed: 19528516 |
| Amantadine provides symptomatic benefit for drug-induced parkinsonism without worsening psychosis | Class III, Level C | Silver H, Geraisy N. J Clin Psychiatry 1995 PubMed: 7615484 |
| Anticholinergics (benztropine, trihexyphenidyl) are effective for DIP but limited by cognitive side effects especially in elderly | Class II, Level B | Ward KM, Citrome L. Ther Adv Psychopharmacol 2018 PubMed: 30181862 |
| Quetiapine and clozapine have lowest EPS risk among antipsychotics and are preferred substitutes | Class I, Level A | Leucht S et al. Lancet 2013 PubMed: 23810019 |
| Clozapine has the lowest risk of EPS among all antipsychotics but requires REMS monitoring for agranulocytosis | Class I, Level A | Kane J et al. Arch Gen Psychiatry 1988 PubMed: 3046553 |
| Risperidone produces dose-dependent EPS; higher doses (>6 mg/day) have EPS risk similar to typical antipsychotics | Class I, Level B | Divac N et al. Psychiatr Danub 2014 PubMed: 25191777 |
| Calcium channel blockers (flunarizine, cinnarizine) are important causes of DIP outside the US | Class II, Level B | Bondon-Guitton E et al. Fundam Clin Pharmacol 2011 PubMed: 20608992 |
| Valproate-induced parkinsonism is dose-related and typically reversible with dose reduction or discontinuation | Class III, Level C | Armon C et al. Neurology 1996 PubMed: 8710098 |
| MDS Clinical Diagnostic Criteria distinguish clinically established and probable PD from secondary causes including DIP | Class I, Level A | Postuma RB et al. Mov Disord 2015 PubMed: 26474316 |
| Olfactory testing helps distinguish DIP (normal) from idiopathic PD (impaired) as a supportive clinical tool | Class II, Level B | Morley JF, Duda JE. Mov Disord 2010 PubMed: 20669302 |
| MIBG cardiac scintigraphy shows reduced uptake in PD but normal uptake in pure DIP | Class II, Level B | Spiegel J et al. Mov Disord 2005 PubMed: 15584032 |
| Ondansetron is a safe antiemetic alternative that does not block dopamine receptors and does not cause parkinsonism | Class I, Level A | Kovac AL. Drugs 2000 PubMed: 10776835 |
| Risk factors for DIP include female sex, older age, pre-existing brain injury, and higher DRBA doses | Class II, Level B | Thanvi B, Treadwell S. Postgrad Med J 2009 PubMed: 19789195 |
| Domperidone does not significantly cross the blood-brain barrier and has minimal extrapyramidal side effects compared to metoclopramide | Class II, Level B | Reddymasu SC et al. Expert Opin Drug Saf 2007 PubMed: 17559511 |
| Serial clinical monitoring with UPDRS motor scores recommended to track DIP resolution and identify non-resolving cases requiring DaTscan | Class III, Level C | Expert consensus; movement disorders practice |
CHANGE LOG¶
v1.1 (January 30, 2026)
- Standardized all structured dosing to 4-field :: delimited format (dose :: route :: frequency :: full_instructions) per C1/M1/R3
- Split Benztropine into separate PO (maintenance) and IM/IV (acute) rows for correct route-specific dosing per M3
- Split Diphenhydramine into separate IV/IM (acute) and PO (maintenance) rows for correct route-specific dosing per M3
- Split Ondansetron into separate IV (acute) and PO (maintenance) rows for correct route-specific dosing per M3
- Added ICU coverage for core labs (CBC, CMP, glucose, drug levels, medication reconciliation) relevant to NMS workup per S1/R4
- Added ICU coverage for extended labs (CK, valproic acid level, lithium level) per S1/R4
- Added ICU STAT coverage for Section 3A causative agent management (all 4 interventions) per S2
- Added ICU coverage for ondansetron IV (STAT) and psychiatric status monitoring (URGENT) per S2
- Added ICU URGENT for psychiatry consult and ROUTINE for pharmacy consult in Section 4A per S1
- Added ICU URGENT for psychiatric status monitoring in Section 6 per S1
- Added medication timeline review ICU = STAT per S2
- Used - :: - :: - :: format for non-medication intervention rows (discontinuation/taper orders) per M2
- Added ═══ section dividers before Section B header per R1/R5
- Added PubMed citation links to all 21 references in Section 8 per R2
- Corrected Ward KM citation co-author from "Bhatt DL" to "Citrome L" per accuracy check
- Added CrCl <15 contraindication detail to amantadine dosing instructions
- Updated version to 1.1 and added REVISED date
v1.0 (January 30, 2026) - Initial template creation - Comprehensive coverage of DIP diagnosis, causative agents, and differentiation from idiopathic PD - Detailed medication management including discontinuation strategies and psychiatric substitution - DaTscan and advanced imaging guidance for diagnostic uncertainty - Anticholinergic and amantadine symptomatic treatment with structured dosing - Alternative antipsychotic substitution guidance (quetiapine, clozapine, aripiprazole) - Non-dopaminergic antiemetic substitution (ondansetron, domperidone) - Causative agent reference table with risk stratification - Key distinguishing features table for DIP vs idiopathic PD - 21 evidence-based references
APPENDIX A: Causative Agent Risk Stratification and Substitution Guide¶
High-Risk Agents (Discontinue or Substitute Immediately):
| Causative Agent | Recommended Substitute | Notes |
|---|---|---|
| Haloperidol | Quetiapine or clozapine | Coordinate with psychiatry; haloperidol has highest EPS risk |
| Chlorpromazine | Quetiapine or aripiprazole | Lower-potency typical but still significant EPS risk |
| Fluphenazine (including decanoate) | Quetiapine or clozapine | Decanoate formulation: effects persist weeks after last injection |
| Risperidone (>4 mg/day) | Quetiapine, aripiprazole, or reduce to <4 mg/day | EPS risk is dose-dependent |
| Metoclopramide | Ondansetron (antiemetic); erythromycin or domperidone (prokinetic) | FDA black box warning for prolonged use |
| Prochlorperazine | Ondansetron or meclizine | Common ER prescription for nausea/vertigo |
Moderate-Risk Agents (Reduce Dose or Monitor Closely):
| Causative Agent | Recommended Action | Notes |
|---|---|---|
| Olanzapine | Reduce dose; consider switch to quetiapine | EPS less common than typicals but dose-related |
| Valproate | Reduce to therapeutic minimum; consider alternative mood stabilizer | Parkinsonism typically reversible with dose reduction |
| Lithium | Check level; reduce to minimum therapeutic | Toxicity increases EPS risk |
| Flunarizine/cinnarizine | Discontinue; substitute alternative migraine prophylaxis | Common cause outside US; reversible |
APPENDIX B: DaTscan Interpretation Guide for DIP¶
When to Order DaTscan: - Diagnostic uncertainty between DIP and idiopathic PD - Parkinsonism persists >6 months after causative agent withdrawal - Atypical features suggesting underlying neurodegenerative process - Patient requires urgent diagnostic clarification (e.g., before surgery)
Interpretation:
| DaTscan Result | Interpretation | Clinical Action |
|---|---|---|
| Normal bilateral striatal uptake | Supports pure DIP; presynaptic dopamine neurons intact | Continue observation; expect resolution after drug withdrawal; reassess in 3-6 months |
| Reduced striatal uptake (asymmetric) | Suggests underlying idiopathic PD unmasked by DRBA | Refer to movement disorders specialist; consider levodopa trial; DIP may have unmasked subclinical PD |
| Reduced striatal uptake (symmetric) | May indicate PD or atypical parkinsonism unmasked by DRBA | Movement disorders specialist; further workup for atypical parkinsonism |
Medications That Interfere with DaTscan (Hold Before Study): - Bupropion (hold 2 weeks) - Amphetamines/methylphenidate (hold 2 weeks) - Modafinil (hold 2 weeks) - Cocaine (hold 2 weeks) - Phentermine (hold 2 weeks) - Benztropine and anticholinergics do NOT interfere
DaTscan Does NOT Differentiate Between: - PD and atypical parkinsonism (PSP, MSA, CBD) - all may show reduced uptake - PD subtypes (tremor-dominant vs PIGD)
APPENDIX C: DIP Resolution Timeline and Follow-Up Protocol¶
Expected Resolution Timeline After Drug Withdrawal:
| Timeframe | Expected Clinical Course | Action |
|---|---|---|
| Week 1-2 | Minimal change; may initially worsen slightly after antipsychotic withdrawal | Reassure patient; monitor psychiatric status |
| Week 2-4 | Early improvement in bradykinesia and rigidity expected | Continue symptomatic treatment if needed |
| Month 1-3 | Significant improvement in most patients; tremor may be last to resolve | Consider tapering symptomatic medications |
| Month 3-6 | Full resolution expected in most patients | If persistent, order DaTscan |
| Month 6-12 | Any residual symptoms raise concern for underlying PD | Movement disorders referral; levodopa trial |
| >12 months | Persistent parkinsonism highly suggests underlying PD unmasked by DRBA | Manage as idiopathic PD |
Follow-Up Schedule: 1. 2 weeks post-discontinuation: Psychiatric status, initial motor assessment, medication review 2. 4 weeks post-discontinuation: Motor re-examination, UPDRS scoring, assess functional improvement 3. 3 months post-discontinuation: Comprehensive motor assessment; if not improving, order DaTscan 4. 6 months post-discontinuation: Final assessment; if fully resolved, educate on future medication avoidance 5. As needed: If symptoms recur or new medications started