Table 2. . Recent findings in nondopaminergic treatments for nonmotor symptoms in Parkinson's disease.

Nonmotor symptoms	Nondopaminergic treatment	Mechanism of action	Stage of development	Recent findings	Ref.
Neuropsychiatric symptoms (depression, anxiety, apathy, psychosis)	Pimavanserin	5HT2A inverse agonist	Phase III Under review at US FDA	Significantly reduced PD-psychosis over 6 weeks: -5.79 decrease in SAPS-PD scores compared with -2.73 for placebo (difference -3.06, 95% CI: -4.91 to -1.20; p = 0.001)	[40]
	Rivastigmine	Cholinesterase inhibitor	Clinically available Phase IV ongoing	Ongoing study to reduce development of visual hallucinations in nondemented PD	[41]
ICD	Naltrexone	Opioid antagonist	Clinically available Phase IV	Naltrexone 50–100 mg/day over 8 weeks in PD patients with ICD showed nonsignificant reduction in ICD severity using clinical global impression scale	[42]
Orthostatic hypotension	Midodrine	α1-adrenoceptor agonist	Clinically available Phase II Crossover trial ongoing	Use in PD has not yet been validated in clinical trials. Crossover trial is ongoing: Midodrine 2.5–5 mg given three-times a day for 2 weeks in PD patients	[43,44]
	Droxidopa	Artificial amino acid converted to norepinephrine	Phase III FDA approved	Increase standing systolic blood pressure. Only short-term benefit reported in clinical trials	[45,46]
	Pyridostigmine	Peripheral inhibitor of acetylcholinesterase	Clinically available Phase II ongoing	Symptomatic management of OH. RCT Phase II is ongoing and will assess noninferiority of the effect of pyridostigmine compared with fludrocortisone for 14 days of active treatment in each group	[43,47–48]
Sialorrhea	Glycopyrrolate	Anticholinergic	Clinically available Phase II ongoing	Mean sialorrhea score improved from 4.6 with placebo to 3.8 with glycopyrrolate 1 mg three-times daily for 4 weeks. Phase II assessing glycopyrrolate 1.5 mg three-times daily for 90 days is ongoing	[49,50]
	Botulinum toxin	Inhibition of acetylcholine release from nerve terminals	Clinically available 2 Phase III trials ongoing	A/Abo 250 U or B/Rima 2500 U injections in PD were effective in 89% of treatments. The overall mean duration was 87 days similar for both serotypes (p = 0.392). Injection-related adverse effects complicated 1.5% of treatments (pain at injection sites, subcutaneous hematoma and mouth bleeding). No patients reported dysphagia or facial weakness	[51–53]
Mild cognitive impairment	Memantine	NMDA receptor antagonist	Clinically available Phase III	Memantine 20 mg/day improved choice reaction time, immediate and delayed word recognition	[54]
	Rivastigmine	Cholinesterase inhibitor	Clinically available Phase III	28 PD patients with MCI treated with rivastigmine (patch) 9.5 mg/day (4.6 mg/day during the initial 4 weeks); however, only a trend toward improved global rating of cognition was seen versus placebo after 24 weeks	[55]
PD dementia	Donepezil	Cholinesterase inhibitor	Currently available Phase II ongoing	Phase II study ongoing comparing donepezil 23 mg versus 10 mg once a day	[56]
	Rivastigmine	Cholinesterase inhibitor	Currently available	Rivastigmine 3 mg orally twice daily for 12 months showed higher MOCA and reduced number of falls compared with placebo	[57]
	SYN120	Dual 5-HT6/5-HT2A antagonist	Phase II ongoing	A Phase II in PDD patients treated with a stable dose of cholinesterase inhibitor is ongoing	[58,59]
Overactive bladder	Botulinum toxin	Inhibition of acetylcholine release from nerve terminals	Currently available 2 Phase IV trials are ongoing	Level A recommendation – effective for overactive bladder. There are 2 Phase IV trials currently active for neurogenic bladder in PD patients	[60,61]
Pain	Oxycodone-Naloxone	Opioid analgesic (oxycodone) with opioid receptor antagonist (naloxone)	Clinically available Phase II ongoing	No significant difference compared with placebo. Reduced pain scores in a smaller trial (fewer side effects)	[62–64]
	Botulinum toxin	Inhibition of acetylcholine release from nerve terminals	Clinically available Phase IV ongoing	A double-blind randomized crossover study is currently ongoing (onabotulinum toxin A)	[65]

Clinically available: but off-label use in this indication.

A/Abo: Abobotulinumtoxin A; B/Rima: Rimabotulinumtoxinb B/Rima; ADL: Activities of daily living; ICD: Impulse control disorder; MCI: Mild cognitive impairment; MMSE: Mini-mental state examination; MOCA: Montreal cognitive assessment; OH: Orthostatic hypotension; PD: Parkinson's disease; PDD: Parkinson's disease dementia; RCT: Randomized controlled trial; SAPS-PD: Parkinson's disease-adapted scale for assessment of positive symptoms.