Goal: Restore dopaminergic tone in the striatum. Drug selection depends on age, symptom severity, and side-effect profile.

Motor complications develop in ~50% of patients after 5 years and up to 80% after 10 years of levodopa therapy. They result from progressive nigrostriatal degeneration and pulsatile dopamine receptor stimulation.

Types of Motor Fluctuations

• Wearing off (end-of-dose deterioration): Predictable return of symptoms before next dose — most common motor complication; managed by increasing dose frequency, adding COMT inhibitor (entacapone), MAO-B inhibitor, or dopamine agonist
• On-off fluctuations: Unpredictable, sudden switches between “on” (mobile) and “off” (immobile) states — not related to dosing schedule; may require apomorphine rescue injections, Duopa pump, or deep brain stimulation
• Delayed-on / dose failure: Delayed or absent onset of effect — often due to protein competition for absorption; take levodopa 30–60 min before meals
• Freezing of gait: Sudden inability to initiate or continue walking — occurs in both on and off states; may worsen with levodopa

Levodopa-Induced Dyskinesias

• Peak-dose dyskinesias: Choreiform movements at peak plasma levels — most common type; reduce individual levodopa dose, add amantadine
• Diphasic dyskinesias: Occur at rising and falling drug levels (beginning and end of dose); often dystonic/ballistic in legs — more difficult to treat
• Off-period dystonia: Painful dystonia (often foot) in early morning before first dose — treat with controlled-release levodopa at bedtime or early-morning dose

Management Strategies for Motor Complications

• Fractionate levodopa doses (smaller, more frequent dosing)
• Add entacapone or opicapone (COMT inhibitor) to extend “on” time
• Add MAO-B inhibitor (rasagiline, safinamide) for wearing off
• Amantadine — first-line for levodopa-induced dyskinesias
• Apomorphine SC injection or sublingual film — rapid rescue for off episodes
• Duopa (carbidopa-levodopa intestinal gel) — continuous jejunal infusion for advanced fluctuations
• Deep brain stimulation (STN or GPi) — for medically refractory motor fluctuations and dyskinesias

• Impulse control disorders (ICDs): Pathological gambling, hypersexuality, compulsive shopping, binge eating — occur in ~15–20% of patients on dopamine agonists; screen regularly; treatment = dose reduction or discontinuation
• Dopamine agonist withdrawal syndrome (DAWS): Anxiety, panic, depression, dysphoria, diaphoresis upon abrupt discontinuation — taper slowly
• Hallucinations: More common than with levodopa — visual hallucinations; reduce agonist before reducing levodopa
• Excessive daytime somnolence / sleep attacks: Sudden onset of sleep without warning — especially pramipexole and ropinirole; counsel about driving
• Peripheral edema: Lower-extremity swelling, may be bilateral
• Orthostatic hypotension: Common across all dopaminergic agents
• Retroperitoneal/pulmonary/cardiac valve fibrosis: Historically with ergot agonists (bromocriptine, cabergoline, pergolide) — pergolide withdrawn; non-ergot agonists (pramipexole, ropinirole) are preferred

• Second most common cause of parkinsonism after idiopathic PD
• Caused by dopamine receptor blockade in the striatum
• Typically symmetric (unlike idiopathic PD) and may lack rest tremor
• Usually develops within weeks to months of starting the offending agent
• DaTSCAN is normal in drug-induced parkinsonism (vs. abnormal in PD) — helpful for distinguishing the two

Common Offending Agents

• Typical antipsychotics: Haloperidol, chlorpromazine (highest risk)
• Atypical antipsychotics: Risperidone, olanzapine (moderate risk)
• Antiemetics: Metoclopramide, prochlorperazine (cross BBB)
• VMAT2 inhibitors: Tetrabenazine, valbenazine, deutetrabenazine (deplete presynaptic dopamine)
• Others: Valproate, lithium (rare)

Safe Medications in PD Psychosis

• Quetiapine: Low D2 affinity — most commonly used; does NOT significantly worsen parkinsonism
• Clozapine: Only FDA-approved antipsychotic for PD psychosis — requires REMS program (weekly CBC for agranulocytosis monitoring); most effective but underused due to monitoring burden
• Pimavanserin: Selective 5-HT2A inverse agonist — FDA-approved for PD psychosis; NO dopamine receptor blockade; takes 4–6 weeks for effect; QT prolongation risk

Tardive Dyskinesia — Additional Details

• Risk factors: Older age, female sex, longer duration of D2 blocker use, higher doses, mood disorders, diabetes
• Mechanism: Dopamine receptor supersensitivity from chronic blockade
• Valbenazine: Selective VMAT2 inhibitor; once daily; well-tolerated; FDA-approved 2017
• Deutetrabenazine: Deuterated form of tetrabenazine; better tolerability (longer half-life, less peak-dose side effects); twice daily; FDA-approved for TD and Huntington chorea
• Do NOT treat TD with anticholinergics (may worsen it) — unlike acute dystonic reactions
• TD may be irreversible even after stopping the causative agent

• Chorea: VMAT2 inhibitors are first-line
  • Tetrabenazine: First FDA-approved drug for Huntington chorea (2008); depletes presynaptic monoamines; short half-life (3x/day dosing); causes depression, parkinsonism, akathisia — BLACK BOX warning for suicidality; requires CYP2D6 genotyping
  • Deutetrabenazine: Deuterated tetrabenazine with longer half-life (2x/day); better tolerability; also FDA-approved for Huntington chorea
• Antipsychotics for chorea + psychosis/behavioral disturbances — haloperidol, risperidone, olanzapine
• Benzodiazepines may help chorea and associated anxiety
• Depression: SSRIs/SNRIs (extremely common in HD, screen regularly)
• Irritability/aggression: SSRIs, atypical antipsychotics
• No disease-modifying therapy currently available

Focal Dystonia

• Botulinum toxin injections: First-line for cervical dystonia, blepharospasm, spasmodic dysphonia, writer’s cramp
• Botulinum toxin blocks presynaptic acetylcholine release at the NMJ
• Effect onset: 2–5 days; peak: ~2 weeks; duration: 3–4 months
• Antibodies to botulinum toxin can develop → switch serotype (type A → type B)

Generalized Dystonia

• Anticholinergics (trihexyphenidyl): Most effective oral agent, especially in children and young adults; titrate slowly; adults tolerate less well
• Baclofen: GABA-B agonist; helpful adjunct
• Benzodiazepines: Clonazepam for adjunctive benefit
• Deep brain stimulation (GPi): Highly effective for DYT1 dystonia; can help other generalized forms

Dopa-Responsive Dystonia (DRD / Segawa Disease)

• Always trial levodopa in any child or young adult with unexplained dystonia
• Autosomal dominant; GCH1 gene (GTP cyclohydrolase I deficiency) — most common cause
• Diurnal fluctuation: symptoms worse in the evening, improve with sleep
• Dramatic, sustained response to LOW-dose levodopa — hallmark of the disease
• Unlike PD, does NOT develop motor complications with chronic levodopa use
• DaTSCAN is normal (intact presynaptic dopamine terminals)

• First-line agents:
  • Propranolol: Non-selective beta-blocker; 60–320 mg/day; most evidence; also available as long-acting formulation; avoid in asthma, bradycardia, diabetes (masks hypoglycemia)
  • Primidone: Anticonvulsant (metabolized to phenobarbital and PEMA); start at very low dose (25 mg at bedtime) to avoid initial “first-dose phenomenon” (severe sedation, nausea, ataxia); equally effective as propranolol
• Second-line agents:
  • Topiramate: Modest benefit; weight loss side effect may be beneficial or detrimental
  • Gabapentin: Mild benefit as monotherapy; may be used as adjunct
  • Benzodiazepines (alprazolam, clonazepam): For refractory or situational tremor
• Botulinum toxin: Useful for head/voice tremor that does not respond well to oral medications; hand tremor treatment limited by weakness side effect
• Surgical: DBS (VIM thalamus) or MRI-guided focused ultrasound thalamotomy for medically refractory cases