by Markos Poulopoulos, M.D.
Introduction
James Parkinson, in his pivotal work “An Essay on the Shaking Palsy” (published in 1817), was the first to recognize the condition that later was named after him.
He defined it as “involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards: the senses and intellects being uninjured.” He then noticed that “the sleep becomes much disturbed,” “the bowels, in most cases, demand stimulating medicines of very considerable power,” and “the urine is passed involuntarily; and at the last, constant sleepiness, with slight delirium, and other marks of extreme exhaustion” (1).
Despite his above observations, little attention was given to the non-motor manifestations of Parkinson disease up until the last 10-15 years. For quite a long time, the scientific focus was heavily on the motor symptoms, which are still used for making the diagnosis (tremor, stiffness/rigidity, slowness/bradykinesia and gait instability). One could say that we were only looking at the tip of the iceberg.
But there is so much more than the physical symptoms, other difficulties that are far more difficult to deal with and cry for more vigorous research and effective treatment development. Psychosis is perhaps the most problematic and intrusive constellation of symptoms, and the subject of this discussion.
What do we mean by psychosis?
Psychosis in Parkinson disease is defined (2) as the presence of at least one of the following symptoms:
⦁ Illusions – This is when you mistake a real object for something else.
⦁ False sense of presence passage (hallucinations) – This when you think there is somebody behind you, or a vague figure is quickly passing by your side. However, when you turn your head to look at it, there is nothing there.
⦁ Hallucinations – This is when you see (less often hear, smell or feel) people or animals typically in front of you that clearly do not exist, and there is no other real object to be mistaken for what you experience.
⦁ Delusions – This pertains to unusual, disruptive beliefs or ideas, usually of a paranoid nature, e.g. persecution, theft, infidelity.
We need to highlight the importance of early recognition and treatment of even benign aspects such as illusions. There is about an 80% chance for these to progress to more complex and persistent symptoms such as hallucinations and delusions, which in turn can be very difficult to treat and have a significant impact on your life and that of your family. If psychosis gets out of hand, it is usually a reason for nursing home placement, and results in an increased rate of other complications, including decreased survival. For example, one may lose insight and firmly believe that the hallucinations (people or animals) are real, react by attacking them or running away from them, and subsequently fall and break a hip. These events can lead to a domino effect with potentially serious complications.
Hence, knowing the nature of psychosis will help the doctors, patients, and care givers to ask pertinent questions in search of subtle signs that would otherwise go unnoticed. It is always better to treat early, rather than late.
How frequent is psychosis?
Overall, psychosis can be present in up to 60% of Parkinson disease patients at some point in time. The more fearsome aspect is visual hallucination, which can be present in 7-25% of patients with Parkinson disease. However, if we consider only patients with dementia (so-called Parkinson disease dementia), hallucinations have a frequency from 40 to 80% (3).
Psychosis is more likely to happen when a patient with Parkinson disease also has dementia. However, it is also well documented in patients with Parkinson disease without dementia. In this situation, psychosis can happen in 20% of patients. In more detailed breakdown, frequency of visual hallucinations is about 13%, auditory hallucinations 7%, illusions 7%, and paranoia 5% (4).
Other non-motor manifestations of Parkinson disease that sometimes predict the development of psychosis are REM sleep behavior disorder (acting out the dream content) and depression/ anxiety.
Do medications play a role? Yes and no.
The answer is yes for most medications, and debatable for carbidopa/levodopa. Although the common practice is to try to reduce the dose or stop medications in hopes of decreasing or stopping the psychosis (see management section), there is evidence that psychosis can happen before the start of any treatment with such medications. It is intriguing that psychosis may happen in up to 40% of drug-naïve patients, as opposed to 5% of individuals without Parkinson disease. In this scenario the good news is that insight is almost always retained, and the type of psychosis is by and large a simple sense of presence or feeling that somebody is passing by (rarely visual hallucination) (5).
What can we do? How can we treat it?
⦁ Knowledge – First of all, knowledge of the nature of psychosis, being able to recognize and communicate its existence without guilt or fear, is paramount and the starting point.
⦁ Search for triggers – The doctor should work with the caregiver and the patient in an attempt to identify potential triggers such as infections, dehydration, insomnia, malnutrition, new medications/dose escalation, home/environmental changes, bereavement, and exacerbation of depression.
⦁ Ideally, a team approach – Behavioral care, case management, and physical, speech, language, and occupational therapy aiming at an individualized treatment plan to relieve distress, provide direction, promote adaptation, and optimize quality of life.
⦁ Decrease or stop medications for Parkinson disease (3) – Typically, we wean off, or at least decrease the usual culprits with first and foremost the dopamine agonists (e.g. pramipexole/Mirapex, ropinirole/Requip), anticholinergics (e.g. trihexyphenidyl/Artane, amantadine), and other medications we may use to treat Parkinson disease. Carbidopa/levodopa (Sinemet) is the last medication that should be decreased, and certainly never stopped. There is no clear evidence that this medication can definitely aggravate psychosis. Easily said, but it is usually difficult to implement the above, since decreasing anti-Parkinson medications will lead to worsening of the physical performance (tremor, gait, balance, and overall movement).
⦁ Add medications that mitigate or stop psychosis (brand name in parentheses) (3)
⦁ rivastigmine (Exelon): In a 24-week, prospective, placebo-controlled trial, this medication, designed as a memory enhancer, both improved memory and decreased hallucinations (6).
⦁ quetiapine (Seroquel): The evidence is rather equivocal in favor of this medication directly improving visual hallucinations based on studies (7). However, it is widely used in clinical practice with good results based on anecdotal and personal experience. The main reasons are the ease of use and titration, and the favorable side effect profile (compared to all the other antipsychotics, it has the least potential for increased mortality).
⦁ clozapine (Clozaril): This medication has, so far, the best evidence with respect to efficacy reducing visual hallucinations (8). However, frequent blood draws, the rare but very significant danger of reducing white blood cells that fight infections, frequent drowsiness, weight gain, and dizziness make it not the first choice for most doctors.
New treatment
Pimavanserin (Nuplazid) is the latest medication tested for treatment of visual hallucinations in Parkinson disease.
Based on a 6-week trial (randomized, double-blind, placebo-controlled) on a total of 200 patients (the largest number tested compared with the other medications listed above, apart from the rivastigmine trial), it did produce a statistically significant reduction in hallucinations, improved night time sleep, and decreased daytime sleepiness (9).
Furthermore, pimavanserin did not aggravate the motor symptoms of Parkinson disease and was overall well tolerated, probably better than quetiapine and clozapine, by extrapolation. This is likely due to a pharmacological action that differs from the other antipsychotic medications. All of the others block the various dopamine receptors in the brain and typically worsen Parkinson disease symptoms, since the levodopa (which converts into dopamine in the brain) cannot act on the dopamine receptors because they are occupied (blocked) by the antipsychotics. Pimavanserin does not act on dopamine receptors. Rather, it acts on serotonin receptors (specifically 5-HT2a). Pimavanserin may cause leg swelling (7%), nausea (7%), confusion (6%), and constipation (4%).
The pressing need for better treatments for psychosis in Parkinson disease led to FDA discussion for early approval on May 1, 2016
In conclusion, it is very important for patients and caregivers to report to the doctor symptoms in keeping with psychosis, so that we can search for triggers (as mentioned above), monitor symptom evolution and prevent/treat, if possible.
References
1. James Parkinson. An Essay on the Shaking Palsy. Neuropsychiatric classics. 1817.
2. Bernard Ravina et al. Diagnostic Criteria for Psychosis in Parkinson’s Disease: Report of an NINDS, NIMH Work Group. Movement Disorders, Vol. 22, No. 8, 2007, pp. 1061–1068.
3. Dag Aarsland et al. Psychiatric issues in cognitive impairment. Movement Disorders, Vol. 29, No. 5, 2014. Pages: 651-662.
4. Angela H Lee et al. Psychosis in Parkinson’s Disease Without Dementia: Common and Comorbid With Other Non-Motor Symptoms. Movement Disorders, Vol. 27, No. 7, 2012. Pages: 858-863.
5. Javier Pagonabarraga et al. Minor Hallucinations Occur in Drug-Naïve Parkinson’s Disease Patients, Even From the Premotor Phase. Movement Disorders, Vol. 31, No. 1, 2016. Pages 45-52.
6. Burn D et al. Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson’s disease. Movement Disorders 2006; 21:1899-1907.
7. Ondo WG et al. Double-blind, placebo-controlled, unforced titration parallel trial of quetiapine for dopaminergic-induced hallucinations in Parkinson’s disease. Movement Disorders 2005; 20:958-63.
8. The Parkinson study group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. NEJM 1999;340:757-63.
9. Cummings J. Pimavanserin for patients with Parkinson’s disease psychosis: a randomized, placebo-controlled phase 3 trial. Lancet 2014,(8);383:533-540.
