Pharmacology · Antiparkinson Drugs

Non-Motor Symptoms

Pharmacological management of dementia, psychosis, depression, and autonomic dysfunction

Non-motor symptoms — dementia, psychosis, depression, orthostatic hypotension, and restless legs syndrome — are major determinants of quality of life in Parkinson's disease and require targeted pharmacological management distinct from motor therapy.
Rivastigmine is the only FDA-approved cholinesterase inhibitor for Parkinson's disease dementia; the transdermal patch is preferred for GI tolerability; donepezil is commonly used off-label.
Antipsychotic drug selection is critical: typical antipsychotics and risperidone block striatal D2 receptors and cause severe motor deterioration — they are absolutely contraindicated; only clozapine, quetiapine, and pimavanserin are acceptable.
Pimavanserin is the preferred agent for Parkinson's disease psychosis — it is an FDA-approved serotonin 5-HT2A inverse agonist with zero dopamine receptor activity, producing no motor worsening.
SSRIs and SNRIs are preferred for depression (avoid tricyclics for their anticholinergic burden and cardiac effects); dopamine agonists treat restless legs syndrome using the same agents that address motor symptoms.

Symptom	First-Line Drug	Key Points
Dementia	Rivastigmine	Only FDA-approved cholinesterase inhibitor for Parkinson's disease dementia; patch preferred for tolerability
Psychosis	Pimavanserin	Serotonin 5-HT2A inverse agonist; no dopamine blockade; no motor worsening; only drug approved for Parkinson's disease psychosis
Psychosis (alt)	Quetiapine / Clozapine	Low dopamine D2 affinity atypicals; clozapine requires agranulocytosis monitoring
Depression	SSRIs / SNRIs	Preferred; avoid tricyclics (anticholinergic burden, cardiac effects)
Orthostatic hypotension	Midodrine / Fludrocortisone / Droxidopa	Midodrine: alpha-1 agonist; fludrocortisone: volume expansion; droxidopa: norepinephrine precursor
Restless legs syndrome	Dopamine agonists	Pramipexole and ropinirole approved for restless legs syndrome; same agents used for motor symptoms

Suggested References

Author / Organization	Title	Source
Katzung BG, Trevor AJ	Basic and Clinical Pharmacology, 15th ed.	McGraw-Hill, 2021
Brunton LL, Knollmann BC	Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th ed.	McGraw-Hill, 2018
Le T, Bhushan V	First Aid for the USMLE Step 1	McGraw-Hill, current edition
Connolly BS, Lang AE	Pharmacological treatment of Parkinson disease: a review	JAMA. 2014
Cummings J et al	Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial	Lancet. 2014