The Role of the Pharmacist in the Management of Psychosis in Parkinson’s Disease

Introduction

Parkinson disease psychosis (PDP) represents a common and disabling nonmotor complication, affecting up to 60% of patients over the course of their illness.¹ Hallucinations, illusions, and delusions increase caregiver burden, institutionalization risk, and mortality.^1,2 Unlike primary psychotic disorders, PDP arises in the context of chronic neurodegeneration and dopaminergic and thus possesses significant management challenges for clinicians.³

Once recognized solely as a basal ganglia disorder, PD is increasingly recognized as a multisystem neurodegenerative disorder. Evidence supports the gastrointestinal origin hypothesis, wherein misfolded α-synuclein appears in the enteric nervous system years before motor symptoms, traveling via the vagus nerve to the brainstem and eventually midbrain and limbic structures.⁴ As Lewy pathology ascends, it disrupts dopaminergic, serotonergic, and cholinergic activity important for cognition, visual processing, and perception.^3-5

Thus, PDP represents both disease-driven pathology and treatment-related dopaminergic overstimulation. Because the same dopaminergic medications improving bradykinesia and rigidity (eg, levodopa, dopamine agonists) may precipitate or worsen hallucinations and delusions, pharmacists must balance motor benefit against neuropsychiatric safety. Pharmacists play a critical role in this process by identifying medications that worsen psychosis, optimizing dopaminergic regimens, recommending appropriate antipsychotic therapy, and monitoring for adverse effects for patient safety.^3,6 

Pathophysiology of PDP

The development of PDP involves disruption of dopaminergic, serotonergic, and cholinergic systems, each influenced by the progression of PD and the medications used to treat it.^3,5,7 Degeneration of the substantia nigra results in severe deficiency of dopamine in motor pathways causing bradykinesia and rigidity.⁷ In mesolimbic pathways, this deficiency results in postsynaptic upregulation and hypersensitivity of dopamine receptors causing psychiatric disturbances such as psychosis.^3,7 

As Lewy pathology spreads to limbic and cortical areas including the amygdala and visual association cortex, vulnerability increases to dopamine-mediated psychiatric disturbances.^4,7

Adding PD medications such as levodopa further increases vulnerability to PDP.⁷

The following medications worsen PDP through dopaminergic overstimulation^6,7:

• Levodopa (high doses): increases synaptic dopamine; induces hallucinations in sensitized mesolimbic pathways.
• Dopamine agonists (pramipexole, ropinirole, rotigotine): strongly linked with hallucinations and impulse-control disorders.
• MAO-B inhibitors (rasagiline, selegiline): increase dopamine by inhibiting metabolism.
• COMT inhibitors (entacapone, opicapone): prolong the activity of levodopa. This increases dopamine peaks.
• Amantadine: an NMDA-glutamate receptor antagonist used as adjunctive therapy for motor symptoms and levodopa-induced dyskinesia; it increases synaptic dopamine release, with associated confusion and visual hallucinations, particularly in elderly patients or those with renal impairment.

Serotonergic System (5-HT₂A Receptors)

Serotonergic disruption contributes prominently to PDP. Imaging studies reveal increased 5-HT₂A receptor binding in frontal and visual cortical regions among patients with PDP-associated visual hallucinations.^8,9 This cortical 5-HT₂A upregulation is believed to alter the process of visual information and lower the threshold for illusions, misinterpretations, and dream intrusion.^8-10

Although rare, the following medications may worsen PDP by increasing serotonergic activity^2,10:

• Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) increase synaptic serotonin in cortical and subcortical pathways. Case reports and small series describe rare complex visual hallucinations during treatment with SSRIs and SNRIs, particularly in neurologically vulnerable or older patients. In PD, heightened serotonergic tone acting on upregulated 5-HT₂A receptors may therefore exacerbate preexisting hallucinations in susceptible patients, so close monitoring and dose adjustment are recommended if PDP worsens after starting or increasing these agents.
• Tricyclic antidepressants (TCAs) combine monoamine (including serotonin) reuptake inhibition with strong anticholinergic effects. Various reports of antidepressant-induced complex visual hallucinations during TCA treatment support that this class can precipitate or aggravate hallucinations in predisposed patients, including those with PD.

Cholinergic System

Acetylcholine supports attention, visuospatial processing, and sensory integration. In the course of PD, decreasing cholinergic activity results in disturbed interpretation of visual input by the brain, with increased susceptibility to hallucinations, particularly in the presence of cognitive impairment.^5,11

The following medications worsen PDP by reducing acetylcholine^5,11,12:

• Anticholinergics (benztropine, trihexyphenidyl) are centrally acting agents that are FDA-approved for Parkinsonian tremor and rigidity. However, they reduce cortical and limbic acetylcholine, which can precipitate or worsen confusion, delirium, and visual hallucinations especially in older adults or patients with underlying cognitive impairment.
• Sedating antihistamines (diphenhydramine, doxylamine) are first-generation antihistamines with strong anticholinergic properties that have the potential to cause confusion and hallucinations in patients with PD.
• Bladder antimuscarinics (oxybutynin, tolterodine) are centrally acting antimuscarinics that are deliriogenic in older adults and have been associated with new-onset confusion and hallucinations.

Antipsychotic Options

When PDP persists despite optimization of dopaminergic therapy and deprescribing of high-risk agents, antipsychotic treatment may be necessary. Pharmacists should prioritize agents that minimize motor worsening.^3,6

Pimavanserin (Nuplazid; Acadia Pharmaceuticals, Inc)

The only medication approved by the FDA specifically for the treatment of hallucinations and delusions associated with PDP is pimavanserin.¹³ It is a selective 5-HT₂A inverse agonist with partial activity at 5-HT₂C receptors, without significant dopaminergic, histaminergic, muscarinic, or adrenergic receptor blockade. By dampening overactive 5-HT₂A signaling in cortical and limbic regions, pimavanserin improves psychosis without worsening motor symptoms.^13-15 

Key pharmacist considerations include QT interval prolongation, potential interactions with strong cytochrome P450 3A4 modulators, edema, and confusion.^13-15

Clozapine (Clozaril; HLS Therapeutics, Inc)

Clozapine remains one of the most effective antipsychotics for PDP, producing significant improvement in hallucinations and delusions without worsening motor symptoms. Its unique receptor profile explains its superiority in PDP.¹² Clozapine has minimal dopamine D₂ receptor antagonism, limiting further deterioration in motor function. Rather, its anti-psychotic activity arises principally from potent 5-HT₂A antagonism, dopamine D₄ receptor antagonism histamine H₁, α₁-adrenergic, and muscarinic receptor antagonism.¹²

Because of this receptor profile, clozapine is able to diminish hallucinations and delusions at very small doses without severe motor impairment. While no longer requiring ANC level monitoring, routine review is still recommended to detect neutropenia.¹²

Quetiapine

Quetiapine (Seroquel; AstraZeneca) is widely used off label for PDP because it does not require blood monitoring and has relatively low dopamine affinity.¹⁶ It has low-affinity dopamine blockade, strong 5-HT₂A antagonism, and high H₁ and α₁-adrenergic receptor affinity. It may reduce hallucinations and nighttime agitation. Sedation and orthostasis are common dose-limiting adverse effects.¹⁶

Emerging Therapies

Xanomeline–trospium (Cobenfy; AbbVie Inc), is the first FDA-approved antipsychotic for schizophrenia to act without dopamine D₂ blockade but instead preferentially stimulates central M₁ and M₄ muscarinic receptors while blocking peripheral M₂/M₃ receptors.¹⁷

The preclinical and clinical data suggest that M₁/M₄ activation can reduce psychotic symptoms and improve cognition by modulating cortico-striatal and mesolimbic dopamine and glutamate signaling, without worsening parkinsonism. Because cholinergic dysfunction and altered muscarinic signaling are also implicated in PD and related psychoses, M₁-agonist strategies such as Cobenfy are now being actively investigated for disorders including PD.² This agent has been proposed as a future potential option for PDP. However, no randomized trials in PDP have been completed yet, so its use in this setting remains theoretical and investigational.¹⁷

The Pharmacist’s Role in PDP Care

Across inpatient, outpatient, and behavioral health settings, pharmacists can materially improve outcomes for patients in multiple ways. Pharmacists can perform complete medication reconciliation to identify dopamine-receptor blocking agents, anticholinergics, and high-risk sedative medications known to exacerbate psychosis or parkinsonism. They should recommend rational deprescribing and dose optimization of dopaminergic therapies in collaboration with neurology and psychiatry.

Additionally, the selection and monitoring of antipsychotic therapy, including counseling regarding onset of effect, adherence, dose titration, and adverse effects such as QT prolongation, orthostasis, sedation, and hematologic toxicity, all fall within the role of the pharmacist. Finaly, educate patients and caregivers about the recognition of hallucinations, sleep hygiene, reducing environmental triggers, and fall prevention.

Conclusion

PDP is a common and disabling complication that is driven by dopaminergic sensitization, serotonergic 5-HT₂A overactivity, and cholinergic deficits. Early involvement by the pharmacist is crucial in identifying medication triggers, supporting evidence-based adjustment of dopaminergic therapy, and implementing antipsychotic regimens such as pimavanserin, clozapine, and quetiapine that minimize motor deterioration. By incorporating pathophysiologic knowledge into medication management and patient education, pharmacists can make a big difference in the quality of life of PDP patients and their caregivers.

REFERENCES

1. Forsaa EB, Larsen JP, Wentzel-Larsen T, et al. A 12-year population-based study of psychosis in Parkinson disease. Neurology. 2010;75(2):127-132. doi:10.1001/archneuro.2010.166

2. Samudra N, Patel N, Womack KB, Khemani P, Chitnis S. Psychosis in parkinson disease: a review of etiology, phenomenology, and management. Drugs Aging. 2016;33(12):855-863. doi:10.1007/s40266-016-0416-8

3. Seppi K, Weintraub D, Coelho M, et al. The Movement Disorder Society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson’s disease. Mov Disord. 2011;26(suppl 3):S42-S80. doi:10.1002/mds.23884

4. Hawkes CH, Del Tredici K, Braak H. Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol. 2007;33(6):599-614. doi:10.1111/j.1365-2990-2007.00874.x

5. Perry EK, Perry RH, Kerwin JM, et al. Cholinergic correlates of cognitive impairment in Parkinson’s disease: comparisons with Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 1995;58(3):300-306.

6. Meltzer HY, Mills R, Revell S, et al. Pimavanserin, a serotonin2A receptor inverse agonist, for the treatment of Parkinson’s disease psychosis. Neuropsychopharmacology. 2010;35(4):881-892. doi:10.1038/npp.2009.176

7. Ballanger B, Strafella AP, van Eimeren T, et al. Serotonin 2A receptors and visual hallucinations in Parkinson disease. Arch Neurol. 2010;67(4):416-421. doi:10.1001/archneurol.2010.35

8. Rasmussen NB, Ebdrup BH, Pinborg LH, et al. Increased frontal serotonin 2A receptor binding in patients with Parkinson’s disease and visual hallucinations. Front Neurol. 2016;7:208.

9. Cho SS, Pellecchia G, Ko JH, et al. The relationship between serotonin-2A receptor and cognitive functions in Parkinson’s disease with visual hallucinations. Mov Disord Clin Pract. 2017;4(6):824-831. doi:10.1002/mdc3.12466

10. Cancelli I, Marcon G, Balestrieri M. Factors associated with complex visual hallucinations during antidepressant treatment. Hum Psychopharmacol. 2004;19(8):577-584. doi:10.1002/hup.64

11. Tune LE. Anticholinergic effects of medication in elderly patients. J Clin Psychiatry. 2001;62(suppl 21):11-14.

12. Pollak P. Clozapine in drug-induced psychosis in Parkinson’s disease. Neurology. 2004;63(5):S24-S29.

13. Cummings J, Ballard C, Ravina B, et al. Pimavanserin: potential treatment for dementia-related psychosis. J Prev Alzheimers Dis. 2018;5(4):253-258.

14. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomized, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533-540.

15. Cummings J, Friedman JH, Jankovic J, et al. Pimavanserin in patients with Parkinson’s disease psychosis: results of a phase 2 study. Mov Disord. 2013;28(10):1370-1377.

16. Cross AJ, Ashton CH. Pharmacology and clinical use of quetiapine. Front Psychiatry. 2015;6:49.

17. Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC. Muscarinic acetylcholine receptor agonists as novel treatments for schizophrenia. Am J Psychiatry. 2022;179(9):611-627.