Up to 30% of individuals with Parkinson’s disease (PD) experience psychosis, most commonly visual hallucinations, and 80% of individuals with dementia with Lewy bodies (DLB) – also termed Lewy body dementia (LBD) – have complex visual hallucinations.1 Symptoms of dementia and psychosis can further overlap with those of Alzheimer’s disease. Here, a review of differential diagnoses and medication options for those with Parkinson’s.

Distinguishing Dementia in the Context of Parkinson’s (PDD) and Lewy Bodies (DLB)

Dementia that develops in patients already diagnosed with PD is referred to as Parkinson’s disease with dementia (PDD), while dementia that develops before or at the same time as a motor disorder is diagnosed as DLB, according to the Weill Institute for Neurosciences Memory and Aging Center at the University of California San Francisco. Many investigators consider PD and DLB to be part of the same disease process continuum, instead of being two distinct diseases. Lewy bodies are accumulations of alpha-synuclein in the brain, which are found in individuals with PD as well as in those with DLB.2

Individuals with PD experience a loss of dopaminergic neurons in the substantia nigra, causing movement symptoms including bradykinesia, dyskinesia, facial masking, tremor, and postural instability, according to the Parkinson’s Foundation. There are also many non-motor symptoms of PD, including anxiety, cognitive changes, fatigue, problems with speech and/or swallowing, and vision changes.3 Dopamine or dopamine agonists are considered the go-to treatment for reducing PD motor symptoms and are also beneficial for non-motor symptoms.

Pharmacologic Therapies for Parkinson’s Disease Dementia and Lewy Body Dementia

Three drugs – clozapine, quetiapine, and pimavanserin – are currently available to treat psychotic symptoms in individuals with Parkinson’s, with varying side effects and efficacy profiles. In a review published earlier this year, Kevin Kyle, MBBCh, and Jeff M. Bronstein, MD, PhD, of the David Geffen School of Medicine at UCLA, discussed the benefits and risks of each of these drugs.Below are the highlights.

“Psychotic symptoms in the context of PDD and DLB present a substantial burden to patients and caregivers, with increased morbidity and mortality risk,” they wrote. “These symptoms present a major therapeutic challenge in terms of balancing risk to benefit ratio in this fragile population.”

Clozapine, which has been used to treat PD-related psychosis since the 1980s, has the strongest evidence for benefit and it may also help with tremors, but patients on the drug must have frequent blood tests to monitor for agranulocytosis, stated Kyle and Bronstein in their review. The main side effects are somnolence and orthostatic hypotension. They noted that no RCTs have been conducted of clozapine for DLB, which “restricts our confidence and guidance” as extrapolated from the literature.1

Quetiapine appears to have a better side effect profile than clozapine, does not require patients to be monitored with blood tests, and is widely used for patients with PD-related psychosis, but the evidence base for its use in PDP and DLB is “ambiguous,” with mixed results from RCTs, according to the Kyle and Bronstein. Quetiapine side effects may include sedation and orthostasis.

The newest FDA-indicated drug for PD-related psychosis is pimavanserin, approved in 2016. Pimavanserin is an inverse 5-HT2A receptor agonist, so it does not block dopamine and does not appear to worsen motor symptoms, noted Kyle and Bronstein. “Pimavanserin’s expedited approval despite only one positive Phase 3 RCT perhaps underscores the substantial unmet need in PDP.” One drawback of the newer drug, they clarified, is that it can require 4 to 6 weeks to take effect. (Editor’s Note: pimavanserin underwent FDA review in spring 2021 for treating dementia-related psychosis but approval has been delayed.)

Other neuroleptics, including olanzapine, have not shown significant benefit and may worsen motor symptoms, they added.

The cholinesterase inhibitors rivastigmine and donepezil are a mainstay of treatment for DLB, and have been shown to improve cognition, but studies in PDD have had mixed results.

Editor’s Note: Kyle and Bronstein’s paper also includes algorithms for treating psychosis in PD and DLB.1

More Treatment Solutions Are Needed for PDD and DLB

Kyle and Bronstein’s review makes it clear that better options are needed for treating psychosis in both PD and DLB and Michael S. Okun, MD, agrees. “Psychosis remains an important treatment hurdle for both Parkinson’s and Lewy Body Dementia,” he told Psycom Pro. “It is a tricky area as many of the treatments can actually make some symptoms worse.” Dr. Oken serves as medical director of the Parkinson’s Foundation and chair of neurology at the University of Florida Health in Gainesville.

“Our most effective drug for both disorders requires weekly blood monitoring and may not be feasible for half or more of families,” says Dr. Okun. “We need to do a better job of educating practitioners of the safe options for care, and we need to encourage industry to continue to develop more solutions to this sometimes vexing problem.”

Medication Management in Patients with PD-related Psychosis or DLB

Test for UTI

Dr. Okun advises that patients with acute psychosis first be tested for urinary tract infection, which can precipitate psychosis. “That is responsible for a good proportion of people with confusion or psychosis acutely,” he explains. “The other thing [to do] is a complete review of the medications.”

Review Full Drug Regimen

Reducing dosages of drugs that can contribute to psychosis – and eliminating them when possible – should be done using a step-by-step approach, he recommends, while adding medications to a patient’s regimen should be done the same manner.

“A lot of times, people jump to the medications before they take stock as to the entire situation,” he notes, pointing out that taking away or adding medications all at once can make it impossible to tell which element of treatment is benefiting patients, or worsening their condition.

Consider Drug Risks versus Benefits for the Individual Patient

“You have to be very careful, and so it’s super important that clinicians are aware of the differences between these three drugs [clozapine, quetiapine, and pimavanserin], the risks and the benefits, and that these are the ones that are applied rather than the classical dopamine blockers,” he adds.

The acetylcholinesterase inhibitors rivastigmine and donepezil can be helpful for psychosis in patients with PD and DLB, and may improve memory as well, according to Dr. Okun. “There’s certainly a subset of people with Lewy bodies that do really well with that medication.”

Quetiapine can help patients with sleep, and this could account for some of the benefits it provides for patients with psychosis, he adds.

Psychosis in DLB can be more challenging to treat than in PD, Dr. Okun notes, because certain medications can make symptoms worse. “Persons with Lewy bodies often have what is called cognitive fluctuations,” he explains. “They can be very sensitive to many medicines.”

Individuals with DLB and PD may also develop a sensitivity to dopamine and dopamine blockers, he adds. “That’s more common with Lewy body dementia than it is with Parkinson’s disease psychosis, and that’s another thing you have to watch out for.”

Finally, Take A Quick but Careful Approach

Clinicians who see psychosis in a patient in their practice should address it aggressively – but carefully, emphasizes Dr. Okun. “It should be, ‘I need to know how you’re doing by the end of this week,’” he advises, when following up with patients. “You need to stay on the care of the person until you’ve got them out of it, but if you do everything at once, it can be a disaster. You really have to be disciplined in your approach to a psychosis patient.”


More resources for caregivers of dementia with Lewy bodies. 

See a related article on our sister site regarding pain management in Parkinson’s disease.

Last Updated: Apr 7, 2021