George T. Grossberg, MD: Hello, I'm Dr. George Grossberg. I'm Professor and Director of the Division of Geriatric Psychiatry in the Department of Psychiatry and Behavioral Neuroscience at St. Louis University School of Medicine. Welcome to episode three of this podcast series entitled Therapeutic Decision Making in Parkinson's Disease Psychosis.

Joining me today is Dr. Raj Pahwa, who's a movement disorder expert and a professor of neurology at the University of Kansas Medical Center in Kansas City, Kansas. Welcome, Raj. It's great to be working with you again today.

Rajesh Pahwa, MD: Thank you for having me.

Dr Grossberg: Great to have you.

In this episode we'll talk about why we treat Parkinson's Disease Psychosis, when to treat it, how to treat it, and what happens if there is coexisting cognitive impairment or dementia. Just to kind of set the background, let's start with how we define Parkinson's disease psychosis. We often focus on the motor symptoms of Parkinson's disease because, after all, it is a degenerative brain disease with motor symptoms, but the non-motor symptoms can be just as disturbing, if not more so.

The 2007 NINDS/NIMH diagnostic criteria for Parkinson's disease psychosis require, at least one of the following symptoms. Hallucinations, which we define as kind of abnormal perceptions without a physical stimulus, most often visual hallucinations. Or delusions which are firm, false beliefs despite evidence to the contrary, most commonly paranoid delusions. Illusions, which are basically misperceptions of real stimuli in the environment. Or a false sense of presence, sensing that someone is around or something is there that really isn't. Very, very importantly, the symptoms occur after a Parkinson's disease diagnosis. They need to be recurrent or continuous for at least one month.

Now, we also know that about half of patients with Parkinson's disease will experience psychotic symptoms sometime during the course of their disease. We also know that Parkinson's disease psychosis is associated with disability relative to activities of daily living. It's also associated with depression or lowered mood, lower quality of life. Of course, these all lead to increased caregiver burden. We also know that undiagnosed, untreated Parkinson's disease psychosis increases the risk of nursing home placement, increases the risk of morbidity, and even increases the risk of mortality.

Raj, you have an excellent case from your clinic. Why don't you share that with us, if you would?

Dr Pahwa: Yeah. Thank you. I would like to talk about this patient of mine, 72 year-old male. He presented for a routine clinic appointment. On discussing with him his Parkinson's symptoms were under good control. He did not have any off time. He did not have any dyskinesias. He was not having any falls. He was independent in his activities of daily living. On questioning, he said yes, he is occasionally having hallucinations. He sees a dog once or twice a week. He knows it is not real since he does not have a dog. Often, when he tries to touch the dog, it disappears. His wife, who's sitting with him, says that she did not even know he was having hallucinations as he had never mentioned this to her. His current medications were carbidopa-levodopa 25-100, one and a half tablets four times a day, sertraline 50mg a day for anxiety, and melatonin, 10mg at bedtime for sleep.

When we examined him, he was alert and oriented. We did a cognitive screen on him using the MoCA and he scored reasonably well. He got a 23 out of 30. On examination, he had a mild resting tremor in his right hand, he had mild bradykinesia and rigidity bilaterally. He had a slightly stooped posture and used a cane occasionally for ambulation. We did some screening labs on him. We did a CBC, a chem profile, a urine analysis, a serum B12 level, and all came back as unremarkable. We discussed with him possibly trying some behavioral therapy, but neither the patient or the wife wanted to pursue it, so we decided to just leave it as it is and follow him back in about his routine follow up in six months.

What happened is, four months after the visit, the wife called saying that her husband has been hallucinating every day. He tries to keep feeding the dog, keeps asking her to buy treats for the dog. He gets agitated when she tells him there is no dog and then they start arguing about it. She had taken him to the primary care physician who had, again, ordered labs, which were unremarkable, and basically told her to call our office for a follow up. We basically brought him in and we decided to intervene pharmacologically mainly because, now, the psychotic symptoms were more persistent, and in addition, they were having a substantial impact not only on the patient but also the caregiver.

Dr Grossberg: That makes a lot of sense. It sounds like, in the beginning, when the psychotic symptoms were not so impactful, you made sure that there weren't any other triggers, whether infections or otherwise, but you kind of let things be. But once the psychotic symptoms became impactful and really started to affect the quality of life and quality of functions of both the patient as well as the care partner, then we really need to intervene.

We have a variety of options. The International Parkinson's and Movement Disorder Society have looked at the data with a variety of antipsychotics that might potentially be appropriate. One of the things that they looked at was what data do we have with clozapine? And they found that clozapine would be clinically useful in scenarios like this. It's shown antipsychotic benefit in patients with Parkinson's disease psychosis in two, not huge, but two significant four-week clinical trials. Unfortunately, we all know the liabilities and how difficult it is to use clozapine in this patient population because of the increased risk of agranulocytosis and the requirement for at least the first six months of weekly white cell counts, weekly blood counts, and monitoring. It's not easy especially for our older patients.

The Society also says that pimavanserin, we should be aware, is now the only FDA-approved agent for Parkinson's disease psychosis. And in a meta-analysis of four clinical trials, all of them found that pimavanserin significantly reduced psychotic symptomatology in this patient population. Just incidentally, some of the data with pimavanserin also showed that it may be protective against orthostasis or orthostatic hypotension, which is fairly common with Parkinson's disease because of the patient's autonomic instability. These were the two drugs that had the best data. One FDA-approved, one would be off-label.

They said that possibly useful is a drug that, Raj, you and I know is used a lot by clinicians. It’s quetiapine, which is usually started at low doses. And the clinical trials have not been statistically significant relative to benefit in Parkinson's disease psychosis. The Society also specifically mentions that olanzapine has not been efficacious, and of course, there's significant risk with all of the atypical antipsychotics, with the black box warning and other issues that relate to that.

Now, let's get back to kind of your case, which I think is a typical but very illustrative case. What did you do? What did you select and what were the things that you thought about in making the decision about how to treat your patient?

Dr. Pahwa: Sure. You brought up as three possible treatments here, pimavanserin, quetiapine, and clozapine. Like you said, for us at this stage, even though clozapine is very effective, the blood monitoring at least for the first six months of every week, plus also keeping track of that can be very cumbersome. I personally usually use clozapine in my patients where I don't have success with other treatments. Quetiapine, it can work at low doses, but the challenge can be if we start at 25, it doesn't work, we have to gradually keep increasing the dose. The challenges that Parkinson's patients have with daytime somnolence, as you mentioned, orthostatic hypertension, et cetera, can be challenging for quetiapine. I, again, use quetiapine as my second line drug mainly because of the potential side effects that it can end up causing because it still does have some dopaminergic blockage that can occur with quetiapine and with Parkinson's where they already have very little dopamine left.

I did pick pimavanserin because it is FDA-approved, it has good data in its efficacy, and it's a single dose, doesn't require titration. I started my patient at 34 mg daily. The wife called a week later saying that he is getting better. In fact, he was not arguing with her as much. At his one month follow up visit, she was very pleased with the result. He was also doing much better. The hallucinations were only occasionally happening. They were not bothersome at all. He was pretty much back to his previous visit, the way he was. The only side effect he complained of was mild pedal edema, which really he did not feel was an issue for him at all.

The good part with pimavanserin is it's usually very well tolerated in our patients. We may see occasional confusion, like we talked about pedal edema, occasional dizziness. Of course, with all antipsychotics, when we first start, some of them have worsening of hallucination, but it is one of the better tolerated medications we have for PD psychosis.

Dr Grossberg: I think to highlight also, I think the really good points you made about quetiapine, which for a lot of people is their go-to drug, is we want to keep in mind that it's a low potency antipsychotic, which means you have to give significant amounts to really get good antipsychotic effects. The more you give and the more problems, as you pointed out, whether it's sedation or orthostasis, which this population already has an issue with. What about the notion of assessing treatment success for Parkinson's disease psychosis? How do you do that?

Dr Pahwa: Yeah. For me, when I talk to my patients, we look at, are the patients having any illusions? Are the patients having hallucinations? If they're having hallucinations, are these bothersome for them? And then we talk about delusions. Usually, to me, delusions are much more challenging and I usually look at it as a urgent treatment, so to speak. Of course, you have that hallucinations where the patient really is very psychotic, maybe agitated, where really that patient needs to go to the ER rather than be treated at home. I pretty much use that. Of course, there is a SAPS-PD scale, PD Psychosis scale that is being used in clinical trials, but to me, talking to the patient and caregiver for me really makes a difference.

The other thing I always like to point out is when we talk about psychosis, we don't always look at complete resolution of the symptoms as long as the symptoms become to a point that again, the patient is aware that these are hallucination. The patient is not getting upset about it, the caregiver can manage it when the patient does have hallucinations, all those work very well.

One of the points I point to my patient, especially my caregivers, is don't argue with the patient when the patient says, "I see a dog." "Okay, yes. There is a dog." Let's change the topic rather than sit and argue with the patient, "There's no dog," which actually makes it worse for the patient. To me, as long as those things are happening, we have pretty good success of therapy.

Dr Grossberg: I think disagreeing often gets them more irritable...

Dr Pahwa: Exactly.

Dr Grossberg: ... more adamant, more adamant about what they... Because they are actually seeing these things and this for them is very, very real and can be very frightening. One of the scenarios I wanted to discuss with you would be the Parkinson's disease patient with psychotic symptoms who maybe also has cognitive impairment, as maybe we're moving into more of the Parkinson's disease dementia or with dementia scenario. How does that impact, for you, therapeutic decision making?

Dr Pahwa: Yeah. Cognitive impairment is definitely a risk factor for hallucinations. In fact, if a patient does come with hallucinations, I always check on their cognitive status, like I did with this patient. But as the dementia sets in, the psychotic symptoms can definitely get worse and patients can have more severe psychotic symptoms with worsening of dementia. The one point to remember is that hallucinations, once a Parkinson's patient has them, do not usually resolve. They usually keep getting worse whether we treat the patient or we don't treat the patient. Our goal is to keep them as functional as possible. As long as we can keep the patient at home, both the patient and family are pretty happy.

One thing to remember is the atypical antipsychotics should be used with caution in patients with dementia and psychosis because of the risk of falls, worsening of cognition, maybe even pneumonia, cardiovascular issues, stroke, and death. This is a caution that definitely needs to be kept in mind. Like with other antipsychotics, pimavanserin has a black box warning that there's an increased mortality in patients with dementia-related psychosis. I like to mention here, it's dementia-related psychosis, not Parkinson's psychosis, because patients with Parkinson's often have dementia and psychosis. When we talk about that, we are really talking about that it should not be used in patients who have dementia without Parkinson's.

Dr Grossberg: Yeah. Those are all, I think, excellent points. What about using the cholinesterase inhibitors as well as memantine? What are your thoughts?

Dr Pahwa: Yeah. Rivastigmine is the only medication we have, which is approved and indicated for PD dementia. Patients with PDP and dementia can have fewer hallucinations where rivastigmine is used for cognitive impairment. There is some data available that rivastigmine itself may help psychosis. There are studies that have shown that combination of pimavanserin and cholinesterase inhibitors can have an additive benefit. To me, that happens is, if a patient has cognitive impairment, once I treat them for their psychosis, I usually add a cholinesterase inhibitor and I prefer going to rivastigmine. If, of course, a patient cannot tolerate rivastigmine, galantamine and donepezil can be used even though they don't have the indication or as good a data as rivastigmine does.

Dr Grossberg: What about adding memantine?

Dr Pahwa: Memantine, of course, is not approved in PD dementia, and of course, we just don't have sufficient evidence for its benefit. Having said that, some of us still end up using it in patients who have severe dementia with the hope that it may help our patients.

Dr Grossberg: Yeah. I think that's a good point. Of course, there have been large recent autopsy studies showing how common it is to have mixed dementias or mixed neurocognitive disorders. When we see that Parkinson's patient who eventually develops dementia, with or without psychosis, it may be that a component of that could be Alzheimer's disease or Alzheimer's dementia. Of course, memantine is indicated for moderate to severe Alzheimer's dementia.

Thank you for explaining things so clearly and thank you for this wonderful discussion. It's nice to be with you again today. Also, we need to thank our listening audience for participating in this activity, and we're going to ask them to continue on to answer the questions that follow and complete the evaluation.