Treatment of Parkinson’s disease psychosis

Authorea preprint 07/12/2017 DOI: 10.22541/au.149987482.25845003

Kevin J. Black, M.D. (ORCiD 0000-0002-6921-9567)

Departments of Psychiatry, Neurology, Radiology, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri, USA.
Campus Box 8134, 660 S. Euclid Ave., St. Louis, Missouri, USA, or kevin@WUSTL.edu.

Copyright © 2017, the author.

Submitted 7/2017 to Medicina Internacia Revuo.

Abstract

Early in the course of Parkinson disease (PD), treatment usually goes well. However, after five to ten years, things start to change as treatment requires higher doses of medications and side effects become more problematic. One of the most difficult problems is the development of hallucinations or delusions. Throughout the 20th century, treatment options were unproven and unsatisfactory, but the past 20 years have brought important changes. Two medications that are well tolerated in PD have now proved efficacious in randomized, controlled trials, and others are in development. Here I summarize this history briefly and provide a general plan for treating the patient with PD complicated by psychotic symptoms.

Keywords from MeSH

"Hallucinations/therapy"[Mesh], "Delusions/therapy"[Mesh], "Parkinsonian Disorders"[Mesh], "Delirium"[Mesh], "Antipsychotic Agents" [Pharmacological Action], pimavanserin

Introduction

James Parkinson's original description of the illness that now bears his name focused on motor signs. However, the 200 years since that description first appeared have revealed that nonmotor features are important in Parkinson's disease (PD) (Kehagia 2016). Among these, one of the most problematic is the development of psychosis. Psychosis primarily refers to hallucinations or delusions; a hallucination is a sensory perception in the absence of a real stimulus, and a delusion is a firm belief in something that is not true despite clear evidence to the contrary. A working group convened by the U.S. National Institutes of Health proposed diagnostic criteria for PD psychosis that included not only these typical psychotic symptoms but also illusions (a misinterpreted real percept, such as thinking that one's bathrobe hung on the door is an intruder) and "presence hallucinations" (the sense that someone else is in the room without seeing anyone) (Ravina 2007). A broad and inclusive case definition is appropriate when the phenomenon under investigation is not well described, but time will tell the appropriate nosological position of these less obviously abnormal features. Although most people with PD do not have psychotic symptoms when assessed cross-sectionally, over time a majority of PD patients will eventually develop psychosis (Forsaa 2010).

First steps

The first step in treating psychosis in PD is diagnosis (see Box 1). First one must exclude other causes of psychosis. Appropriate medical history usually can exclude schizophrenia and psychotic mood disorders fairly easily. Excluding delirium is more important. Delirium is characterized by inattention and disorientation, but often is complicated by hallucinations or delusions. Common causes of delirium include infections, recently-added medications, and electrolyte abnormalities, but the diagnosis is made by the clinical syndrome; one cannot always identify a specific single cause. History, mental status and physical examination often suffice for diagnosis, supplemented as appropriate by laboratory studies (Knysz III 2007).

Once PD psychosis is diagnosed, the next step is to prune the list of antiparkinsonian medications. I generally remove them in the following sequence: anticholinergics, amantadine, and then dopamine agonists. Some clinicians also stop monoamine oxidase inhibitors and catechol-O-methyl transferase (COMT) inhibitors. Parkinsonian symptoms often will increase as a result of these medication changes, requiring increases in levodopa dosage. If psychosis persists after thus simplifying antiparkinsonian treatment, levodopa dosage can be reduced if possible, but often patients already are at the minimum dose tolerated for motor function.

At this stage, adding a medication to treat the psychosis is usually necessary. Of course, as with all treatment decisions in medicine, one must weigh the risks and benefits. Initially, some psychotic symptoms may appear relatively benign, for instance seeing an old friend when no one is present. However, psychotic symptoms tend to worsen over time in terms of frequency, complexity and loss of insight, and some hallucinations and delusions can lead to dangerous behavior. Thus at a minimum, even "benign" hallucinations should be monitored carefully, and treatment is often indicated.

Box 1

Diagnostic criteria for psychosis in Parkinson's disease

Adapted from ref. (Ravina 2007), © 2007, by permission of John Wiley and Sons

  • Presence of any of the following:
    • hallucinations
    • delusions
    • illusions
    • false sense of presence
  • Parkinson's disease (UK Brain Bank criteria for PD) prior to development of psychosis
  • Symptoms must be recurrent or continuous for at least 1 month
  • Not better explained by another illness, such as dementia with Lewy bodies, delirium, major depression with psychosis, or schizophrenia
  • May occur with or without any of the following features:
    • insight
    • dementia
    • treatment for Parkinson's disease

Specific treatment

Poorly tolerated or unproven treatments

Until recently, the only available treatments for psychosis consisted of reducing dopaminergic tone. At its extreme, this consisted of removing all antiparkinsonian medications for a period of time, a so-called "drug holiday." As Friedman observed, however, this was "not a holiday in the usual sense," since motor function quickly worsened (Friedman 1985). In fact, patients could develop a neuroleptic malignant syndrome–like presentation, which occasionally could be lethal. Dopamine D2-like receptor (D2R) antagonists prior to the 1990s all had unacceptabl