Drug-Induced Parkinsonism

Drug induced parkinsonism is a syndrome of bradykinesia, rigidity, tremor and postural instability caused by drugs that block dopamine D2 receptors or deplete presynaptic dopamine. It is the commonest cause of secondary parkinsonism and the second commonest cause of parkinsonism overall, and is often missed.

It occurs in about 15 to 60% of people taking antipsychotics, and accounts for up to a quarter of all parkinsonism in older adults. Risk is higher in older people, women and those with cognitive impairment, and with higher doses of high potency antipsychotics.

Causes. Antipsychotics (first and second generation), metoclopramide, prochlorperazine, domperidone (rare), valproate, lithium, calcium channel blockers such as flunarizine and cinnarizine, amiodarone, tetrabenazine and reserpine.

Course. Onset is within days to 3 months of starting or increasing the drug. Most cases recover within weeks to 6 months of stopping, but in some it persists or unmasks underlying Parkinson disease.

Pathophysiology.

Blockade of striatal D2 receptors reduces the effect of dopamine on the indirect loop of the basal ganglia, producing parkinsonian features without loss of nigral neurons.

Persistence after withdrawal suggests subclinical nigrostriatal degeneration that the drug has unmasked.

• Symmetrical bradykinesia and rigidity, often with postural or action tremor rather than a classical rest tremor.
• Reduced facial expression, soft voice, shuffling gait and reduced arm swing.
• Onset after starting or raising a causative drug, with coexisting akathisia or other drug induced movement disorders in some.
• Cognitive slowing and falls in older adults.

Red flags.

• Fever, rigidity and altered consciousness (neuroleptic malignant syndrome).
• Marked asymmetry, rest tremor or persistence after stopping the drug for 6 months (underlying Parkinson disease).
• Falls, dysphagia or aspiration.

• Clinical diagnosis from the temporal link between drug and onset, plus examination.
• Review all current and recent drugs, including over-the-counter and anti-nausea drugs.
• Dopamine transporter imaging (DAT SPECT) is normal in drug induced parkinsonism and abnormal in Parkinson disease; use it when asymmetry or persistence raises doubt.
• Creatine kinase, renal function and electrolytes when neuroleptic malignant syndrome or dehydration is suspected.
• Cognitive screening in older adults.

Differential diagnosis. Parkinson disease, dementia with Lewy bodies, vascular parkinsonism, progressive supranuclear palsy, neuroleptic malignant syndrome, normal pressure hydrocephalus and depression with psychomotor slowing.

• Stop or reduce the causative drug when possible. For antipsychotics, decide with the psychiatry team and prefer an agent with less D2 blockade, as stopping may relapse psychosis.
• Review stopped drugs at 4 to 8 weeks; recovery may take up to 6 months.
• Procyclidine when the drug cannot be stopped: 2.5 mg orally three times daily, increased by 2.5 mg each day every 2 to 3 days as needed to a usual 10 to 30 mg daily in 3 divided doses. Maximum 30 mg daily. Review need every 3 months and withdraw slowly. Monitor for confusion, constipation, urinary retention, dry mouth, tachycardia and worsening tardive dyskinesia. Avoid in angle closure glaucoma, gastrointestinal obstruction, urinary retention and dementia; use lower doses in older adults.
• Amantadine as an alternative: 100 mg orally once daily for 1 week, then 100 mg twice daily. Maximum 300 mg daily. Monitor confusion, hallucinations, livedo reticularis and oedema. Adjust for creatinine clearance of 30 to 59 mL/min (100 mg daily), 15 to 29 mL/min (100 mg on alternate days); avoid below 15 mL/min; avoid in pregnancy and with epilepsy unless needed.
• Levodopa is generally not used because it can worsen psychosis and recovers poorly.
• Falls prevention, physiotherapy and review of swallowing and nutrition.
• Neuroleptic malignant syndrome: stop the drug, give fluids, cool and admit to intensive care.

Monitoring. Review at 2 to 4 weeks after any change, then at 3 and 6 months; reassess for Parkinson disease if symptoms persist.

Referral and escalation. Neurology for diagnostic doubt or persistent symptoms; psychiatry for antipsychotic choice; emergency care for suspected neuroleptic malignant syndrome.

Special groups. Older adults: highest risk, so use the lowest antipsychotic dose and avoid anticholinergics when possible. Dementia with Lewy bodies: severe sensitivity to antipsychotics.