Psychosis in Parkinson’s disease is not only associated with the use of dopaminergic medications, but it is also part of the disease process itself

A study conducted by researchers from the Parkinson’s Disease and Movement Disorders Research Group at the Sant Pau Research Institute, led by Drs. Jaume Kulisevsky and Javier Pagonabarraga, has concluded that psychosis associated with Parkinson’s disease (PDP) not only arises as a complication of dopaminergic drug use but is intimately related to the brain alterations caused by the disease itself.

The study, published in the journal Nature Reviews Neurology, has identified a pattern of cortical atrophy involving various brain regions that would explain how new stimuli are incorrectly categorized and how aberrant hierarchical predictive processing can produce false perceptions that intrude on consciousness flow.

Psychosis associated with Parkinson’s disease (PDP) is a condition that causes illusions, hallucinations, and delusions in more than half of patients with this neurodegenerative disorder. Although it was long believed to appear in advanced stages of the disease and as a result of treatments, it is now known that it can manifest from early stages and follow a continuum ranging from minor hallucinations to structured hallucinations and delusions.

Dr. Javier Pagonabarraga, the lead researcher of the study, explains that “Parkinson’s patients not only face mobility problems but also mood disorders such as anxiety, depression, and apathy. During the course of the disease, between 40-60% of patients may also experience hallucinations, and less frequently some delusional episodes. Hallucinations and delusions are a hallmark of the disease, which has driven research towards a neurobiological model to better understand these phenomena.”

Initially, it was believed that Parkinson’s disease psychosis was mainly related to the use of dopaminergic medications. However, neuroimaging studies have provided a new perspective, demonstrating that this condition develops from the evolution of brain alterations. It has been discovered that the combined dysfunction of various brain systems, including attention control, sensory processing, limbic structures, along with anomalies in the default mode network and thalamo-cortical connections, create a conceptual framework for understanding how new stimuli can be misinterpreted, causing false perceptions that disrupt consciousness flow. Additionally, this brain dysfunction is exacerbated by the use of dopaminergic medications.

Dr. Pagonabarraga explains that “long before people experience severe hallucinations, they already begin to have more subtle and mild hallucinatory phenomena, which often go unnoticed. Thanks to our studies and those of other researchers, we can now identify these phenomena at an earlier stage, allowing us to intervene and address them before they become severe. It is much better to treat these manifestations when they start to emerge than when they have already fully developed and there is a significant loss of reality consciousness.”

This expert details that psychosis has two different types of symptoms: hallucinations – which are the most frequent in these patients – and delusions. It is a clinical characteristic unique to Parkinson’s disease “that has a very clear impact on the quality of life and has even been shown to increase mortality; therefore, understanding the neurobiological bases, that is, which circuits or which parts of the brain are the ones that cause or trigger a person to have hallucinations, is relevant beyond the disease.”

An Opportunity Window

Up to 60% of Parkinson’s patients present psychosis at some point in the disease, but symptoms do not start abruptly. Long before people have severe hallucinations, they already start to have more subtle and mild hallucinatory phenomena that often go unnoticed. “This, in a way, opens a temporal window where we can intervene by treating them before they evolve and become severe. It is much more effective to treat them when they begin to manifest than when they are already severe and involve the loss of reality consciousness,” adds Dr. Pagonabarraga.

Minor hallucinations are subtle forms of the disorder and can be primarily of two types. On the one hand, those known as presence hallucinations, “which is the sensation that someone is behind you, for example, near a shoulder, even though you know there is no one there. The other type is passage hallucinations, which is the sensation that something is passing by the sides of your body. And it happens, moreover, in a very stereotyped way: from behind forward. Patients have the sensation that there is something passing by the side of their body. Most of the time they say it’s the shadow of a person.”

A previous study by this same research group had already observed that these minor hallucinations were present in 40% of Parkinson’s patients from the first visit, that is, before taking any dopamine-raising drugs.

Dr. Pagonabarraga adds that as the disease progresses, the next step is structured visual hallucinations, “not in the periphery, but in the patient’s visual field. They see animals, people, they can sometimes see faces flying as if they had the silhouette of a flying person or sometimes they see elongated people with an indefinite face and a more defined body. Sometimes they can see small children, for example. And these hallucinations occur mainly inside their home. Initially, patients see them, but they know they are not true and it causes them some discomfort. But if we don’t treat them and do nothing, they tend to progress to more severe forms where they see them much more frequently and are no longer aware that they are false. That’s when they do generate a lot of agitation, concern, distress that needs to be treated with drugs that have a negative effect on the evolution of the disease and on the mortality of patients.” This is why it is important to start treating psychosis early.

These findings not only provide a better understanding of psychosis in Parkinson’s disease but also open the door to new therapeutic strategies that could significantly improve the quality of life of affected patients.

Reference Article:

Pagonabarraga J, Bejr-Kasem H, Martinez-Horta S, Kulisevsky J. Parkinson disease psychosis: from phenomenology to neurobiological mechanisms. Nat Rev Neurol. 2024 Jan 15. doi: 10.1038/s41582-023-00918-8.

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