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  • Review Article
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Parkinson disease psychosis: from phenomenology to neurobiological mechanisms

Nature Reviews Neurology volume 20, pages 135–150 (2024)Cite this article

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Abstract

Parkinson disease (PD) psychosis (PDP) is a spectrum of illusions, hallucinations and delusions that are associated with PD throughout its disease course. Psychotic phenomena can manifest from the earliest stages of PD and might follow a continuum from minor hallucinations to structured hallucinations and delusions. Initially, PDP was considered to be a complication associated with dopaminergic drug use. However, subsequent research has provided evidence that PDP arises from the progression of brain alterations caused by PD itself, coupled with the use of dopaminergic drugs. The combined dysfunction of attentional control systems, sensory processing, limbic structures, the default mode network and thalamocortical connections provides a conceptual framework to explain how new incoming stimuli are incorrectly categorized, and how aberrant hierarchical predictive processing can produce false percepts that intrude into the stream of consciousness. The past decade has seen the publication of new data on the phenomenology and neurobiological basis of PDP from the initial stages of the disease, as well as the neurotransmitter systems involved in PDP initiation and progression. In this Review, we discuss the latest clinical, neuroimaging and neurochemical evidence that could aid early identification of psychotic phenomena in PD and inform the discovery of new therapeutic targets and strategies.

Key points

  • Parkinson disease (PD) psychosis (PDP) comprises a spectrum of illusions, hallucinations and delusions that are associated with PD throughout its course.

  • PDP is attributable not only to the use of dopaminergic drugs but also to inherent disruptions linked to the disease, which lead to dysfunction of neural systems governing visual perception, multimodal sensory integration, reality monitoring and attention.

  • Both minor and structured hallucinations in PD are associated with a pattern of cortical atrophy that includes the cuneus, precuneus, middle occipital gyrus, lingual and fusiform gyri, supramarginal gyrus, angular gyrus, anterior cingulate cortex, hippocampal regions and thalamus.

  • Functional neuroimaging studies indicate that PDP is associated with failure of top-down processing of attentional networks, aberrant coupling of the default mode network with visual networks and disconnection between the thalamus and posterior brain areas, leading to aberrant disinhibition of the default mode network.

  • Cortical cholinergic denervation and elevated levels of 5-HT2A serotonergic receptor binding in the ventral visual pathway, medial orbitofrontal cortex and insula have prominent roles in the development of visual hallucinations.

  • An important advance in the treatment of PDP has been the development of drugs that reduce the activity of cortical postsynaptic 5-HT2A receptors, of which pimavanserin is the most notable.

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Fig. 1: Conceptual framework for the pathogenesis of Parkinson disease psychosis.
Fig. 2: Structural brain changes associated with minor and structured hallucinations.
Fig. 3: Functional connectivity changes associated with Parkinson disease psychosis.
Fig. 4: Neurotransmitter systems involved in Parkinson disease psychosis.

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Acknowledgements

This work was partially supported by funding from Centres de Recerca de Catalunya (CERCA) and Centro de Investigación Biomédica en Red, Enfermedades Neurodegenerativas (CIBERNED).

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Authors and Affiliations

  1. Movement Disorder Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    Javier Pagonabarraga, Helena Bejr-Kasem, Saul Martinez-Horta & Jaime Kulisevsky

  2. Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain

    Javier Pagonabarraga, Helena Bejr-Kasem, Saul Martinez-Horta & Jaime Kulisevsky

  3. Sant Pau Biomedical Research Institute (IIB-Sant Pau), Barcelona, Spain

    Javier Pagonabarraga, Helena Bejr-Kasem, Saul Martinez-Horta & Jaime Kulisevsky

  4. Centro de Investigación en Red — Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

    Javier Pagonabarraga, Helena Bejr-Kasem, Saul Martinez-Horta & Jaime Kulisevsky

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J.P., H.B.-K. and S.M.-H. researched data for the article. All authors contributed substantially to discussion of the content, wrote the manuscript and reviewed and/or edited the manuscript before submission.

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Glossary

Bottom-up processing

Processing of information on the basis of incoming data from the environment to form a perception.

Capgras syndrome

The belief that another person, often a friend or relative, has been replaced by an identical or near-identical impostor.

Complex visual illusions

Illusions in which a real object is perceived as another entity, for example, a lamp in the living room is perceived as a standing person.

Controllability ranking

Quantification of the influence that a brain region has across the rest of the network.

Delusional jealousy

Recurrent suspicions, without justification, regarding the fidelity of one’s spouse or sexual partner.

Delusions of control

The experience that one’s feelings, impulses, thoughts or actions are not one’s own but are being imposed by some external force.

Delusions of reference

The false belief that innocuous events or mere coincidences have strong personal significance.

Delusions of theft

The false belief that someone is stealing one’s belongings.

Dysmorphopsia

A visual illusion in which the shape of an object appears distorted.

Effective connectivity

The influence that a node exerts over another under a network model of causal dynamics, which defines the mechanisms of neuronal coupling.

Endogenous systems

Neuronal networks subserving the processing of internal mentations independently from environmental stimuli.

Exogenous attentional systems

Neuronal networks and engrams involved in directing mental processes towards environmental stimuli.

Fregoli syndrome

The belief that another person, often a friend or relative, is able to disguise themself as an unfamiliar person to influence the behaviour of the patient.

Functional coactivation

Functional interactions among different brain regions.

Intermetamorphosis

The belief that another person, often a friend or relative, has been transformed both physically and psychologically into another person.

Kinetopsia

A visual illusion in which stationary objects seem to be moving.

Metachromatopsia

A visual illusion in which colours of an object appear different from those in reality.

Mirrored-self misidentification

Misidentification and reduplication of oneself in the mirror.

Pareidolias

Visual illusions in which formless visual stimuli, such as clouds, tree bark or patterns in carpets or wallpaper, are perceived as human faces or animals.

Persecutory delusions

Pervasive distrust and suspicion of others such that their motives are interpreted as malevolent (exploiting, harming, threatening or deceiving).

Reduplication of a person

The belief that a double of another person exists. Also known as the syndrome of subjective doubles.

Reduplicative paramnesia

The belief that oneself has been relocated to an identical or near-identical duplicated place.

Sensorimotor delay

Time delay between a perception and movements previously associated with that perception.

Visual hallucinations

Visual perceptions of an animate being, object or event in the absence of any external stimulus.

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Pagonabarraga, J., Bejr-Kasem, H., Martinez-Horta, S. et al. Parkinson disease psychosis: from phenomenology to neurobiological mechanisms. Nat Rev Neurol 20, 135–150 (2024). https://doi.org/10.1038/s41582-023-00918-8

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