Parkinson’s Disease Psychosis
Around 50% of patients with Parkinson’s disease may experience hallucinations and/or delusions over the course of their disease.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dysfunction of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein within dopamine producing neurons.1 Motor features used as part of the Movement Disorder Society diagnostic criteria of PD include the presence of bradykinesia, in combination with either resting tremor, rigidity or both.2
Serotonin Dysfunction in Parkinson’s Disease
Dopamine depletion in the dorsal striatum due to loss of nigrostriatal neurons results in the characteristic motor symptoms of PD. Serotonergic dysfunction, however, is thought to be the underlying cause of visual hallucinations that may be experienced in individuals with PD.1,3 Changes in the early stages of PD suggest a shift toward mesolimbic and mesocortical dysfunction.4 These include diminished expression of serotonin transporter (SERT) in the forebrain, as well as observations of increased serotonergic uptake in the thalamus and raphe nuclei.4,5 SERT expression in the caudate, while preserved in early PD, decreases as PD progresses, correlating with advancing disease stage.6 Furthermore, upregulation of 5-HT2A receptors has been observed in the inferolateral temporal cortex, a critical structure in visual processing, as well as other portions of the ventral pathway, including the bilateral inferior occipital gyrus and right fusiform gyrus in PD patients with visual hallucinations.3,7 This upregulation of 5-HT2A receptors in PD may be a compensatory mechanism.4
Parkinson’s Disease Psychosis (PDP)
Parkinson’s disease psychosis manifests primarily as hallucinations, which are abnormal perceptions without a physical stimulus, in any sensory modality (predominantly visual), and delusions, which are false, fixed idiosyncratic beliefs that are maintained despite evidence to the contrary. Delusions are usually associated with a paranoid theme focused on the partner, such as infidelity or intent of harm.8 Around 50% of patients with PD may experience hallucinations and/or delusions over the course of their disease.9
In 2007, the National Institute of Neurological Disorders and Stroke and the National Institute for Mental Health (NINDS-NIMH) recognized psychosis in PD as a clinically distinct diagnosis from other causes of psychosis, such as schizophrenia or delirium.8 The NINDS-NIMH proposed diagnostic criteria include the presence of one of the following characteristic symptoms that have been recurrent or continuous for at least one month, in a patient with a primary diagnosis of PD: illusions, false sense of presence, hallucinations and/or delusions. Other causes of psychosis (e.g., dementia with Lewy bodies, schizophrenia, schizoaffective disorder, delusional disorder, or mood disorder with psychotic features, or a general medical condition including delirium) must be ruled out.
PD psychosis is progressive.10 Early on, patients tend to see a vague movement in their peripheral vision, as though somebody is passing by them.8 Hallucinations tend to become more fully formed with time, such that patients tend to see animals or small children. A single-center study of 48 participants with PD and a UPDRS thought disorder score of 2 (classified as minor hallucinations in the scale) found that over a 3-year follow-up 81% (39 of 48 patients) progressed to a thought disorder score of 3 (loss of insight) or 4 (delusions).10 Using a composite endpoint, which included neuroleptic use or L-dopa dose reduction, 95% progressed, with only two participants continuing with stable, untreated hallucinations.
Hallucinations and delusions associated with PDP may be associated with worse outcomes for patients and caregivers, including nursing home placement and increased mortality.11-13
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2. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30(12):1591-1601.
3. Huot P, Johnston TH, Darr T, et al. Increased 5-HT2A receptors in the temporal cortex of parkinsonian patients with visual hallucinations. Mov Disord. 2010;25(10):1399-1408.
4. Joutsa J, Johansson J, Seppanen M, Noponen T, Kaasinen V. Dorsal-to-ventral shift in midbrain dopaminergic projections and increased thalamic/raphe serotonergic function in early Parkinson disease. J Nucl Med. 2015;56(7):1036–1041.
5. Albin RL, Koeppe RA, Bohnen NI, et al. Spared caudal brainstem SERT binding in early Parkinson’s disease. J Cereb Blood Flow Metab. 2008;28(3):441–444.
6. Kerenyi L, Ricaurte GA, Schretlen DJ, et al. Positron emission tomography of striatal serotonin transporters in Parkinson disease. Arch Neurol. 2003;60(9):1223–1229.
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.
8. Ravina B, Marder K, Fernandez HH, et al. Diagnostic criteria for psychosis in Parkinson’s disease: report of an NINDS, NIMH work group. Mov Disord. 2007;22(8):1061-1068.
9. Forsaa EB, Larsen JP, Wentzel-Larsen T, et al. A 12-year population-based study of psychosis in Parkinson disease. Arch Neurol. 2010;67(8):996-1001.
10. Goetz CG, Fan W, Leurgans S, Bernard B, Stebbins GT. The malignant course of “benign hallucinations” in Parkinson disease. Arch Neurol. 2006;63(5):713-716.
11. Aarsland D, Larsen JP, Tandberg E, Laake K. Predictors of nursing home placement in Parkinson’s disease: a population-based, prospective study. J Am Geriatr Soc. 2000;48(8):938-942.
12. Wetmore JB, Li S, Yan H, et al. Increases in institutionalization, healthcare resource utilization, and mortality risk associated with Parkinson disease psychosis: Retrospective cohort study. Parkinsonism Relat Disord. 2019;68:95-101.
13. Mantri S, Edison B, Alzyoud L, et al. Knowledge, responsibilities, and peer advice from care partners of patients with Parkinson disease psychosis. Front Neurol. 2021; doi: 10.3389/fneur.2021.633645.