Clozapine in Parkinson's disease: Why, when and how?

[00:00:42] Dr. Joseph Friedman: Thank you for the invitation.

[00:00:43] Dr. Michele Matarazzo: So the title is pretty clear about your opinion. Let's start by the very first word of it, clozapine. What is it and how does it work?

[00:00:51] Dr. Joseph Friedman: So clozapine is an antipsychotic drug that was discovered probably in the 1960s or early 1970s, and it was released [00:01:00] for use in Europe for treating schizophrenia. It turned out to be quite effective. But it had an unexpected side effect of causing a drop in neutrophils. And before this was recognized, a number of people died because of agranulocytosis.

The drug was withdrawn from the market. And then gradually brought back into the market in Europe. It had been being tested in the United States, but withdrawn for several years, but then was re-released because of its effect in treating what was called refractive schizophrenia. So it's a drug that is more potent than any other antipsychotic, and in addition has no extrapyramidal side effects, which was why I was interested in the drug.

[00:01:44] Dr. Michele Matarazzo: Now your point is exactly that one, that we should use it more in the setting of Parkinson's disease. How is this drug useful in Parkinson's disease? And what are the indications in a patient with Parkinson's disease?

[00:01:56] Dr. Joseph Friedman: Well, it's been shown in two double-blind placebo [00:02:00] controlled trials. One in France, one in the United States, showing that it's an effective antipsychotic for people with Parkinson's disease who have psychosis, it not only does not worsen motor function, which almost all the other antipsychotic drugs do, but it actually improves tremor.

And there also are studies showing, including double blind trials, showing that it improves tremor that's not responsive to levodopa. So it has the added benefit of not only treating psychosis, but also improving refractory tremor.

[00:02:32] Dr. Michele Matarazzo: Well, that's a very good point. And actually before this interview, I went out and checked the evidence-based recommendation. And as you were mentioning, it has been shown in double blind randomized clinical trial. And actually it is recommended for psychosis in Parkinson's disease.

And it's also recommended for tremor, for dyskinesia in Parkinson's disease. And as you were mentioning, it works also for tremor, especially for the tremor that is refractory to other types of treatment. So why do you think we are not using that [00:03:00] much more than we do? And actually how much do we use it in clinical practice?

[00:03:04] Dr. Joseph Friedman: Well, this is why I wrote the opinion article because I do a lot of peer review and I've sent several peer review articles about people looking at various aspects of the treatment of Parkinson's disease psychosis with the various antipsychotics.

And in doing that, they would do a review of a database, say for Medicare or a database from an insurance company. And they were talking about thousands of patients being treated and patients were being treated with quetiapine. They were being treated with olanzapine. The more recent studies showed they were treated with pimavanserin and they would say that there weren't enough patients on clozapine that they could even do statistics. So maybe less than a 10th of a percent of patients were treated with clozapine. It was just extraordinary that the drug was just not being used.

[00:03:52] Dr. Michele Matarazzo: And why is that? Do you think it's just because we are afraid of using it because of the side effects you were mentioning before, or maybe there has [00:04:00] never been a lot of interest in using it above other medications such as more modern medication as to once you were mentioning before.

[00:04:07] Dr. Joseph Friedman: I think at least in the United States, that there are a couple reasons. One is it's not approved by the FDA for treatment, and that's because by the time it was shown to be helpful in Parkinson's, it was no longer under patent protection. So it required a large investment to get it approved.

That's one thing. And then people, I think were too concerned about the difficulties of doing the blood monitoring. And the blood monitoring is an issue. Blood needs to be checked for a drop in granulocytes once a week for the first six months, then once every other week for six months, and then every four weeks thereafter.

But it turns out that at least, again, in the United States in Medicare covered patients, it's not that expensive to have blood drawn at home for patients who can't get to the laboratories. So it's really not that cumbersome. And filling out the paperwork that's required [00:05:00] is not that hard. In my office where I have a large number of patients on clozapine, my secretary handles all of that, and the only time I get involved is when there's a questionable drop in the blood count and something needs to be done, medicine needs to be held or something like that. It's actually quite easy to do, but I think people don't investigate that, and I think they use it as an excuse not to prescribe it, that it would be too cumbersome. And even the expense, which is covered by insurance, at least in the States, is considerably less than pimavanserin.

[00:05:33] Dr. Michele Matarazzo: So first of all, this podcast is often very much clinical oriented, so I'm gonna put you in a few possible scenarios and I'm gonna ask you questions in these possible scenarios. So let's say there is a patient with Parkinson's disease psychosis. Is there any possibility that you would prefer using, let's say, quetiopine or pimavanserin above clozapine, or you would say that clozapine should be always the first drug to use?

[00:05:58] Dr. Joseph Friedman: No. Well, I have an [00:06:00] algorithm that I use, which is when the psychotic symptoms are very mild and maybe not even terribly bothersome, but I might want to increase medicines for treating the motor symptoms of Parkinson's, which will make the hallucinations worse. I will usually use pimavanserin because it's so benign and agent it has very few side effects. But it takes about four to six weeks before pimavanserin starts to show whether it's gonna be helpful or not, and it's not always helpful. So you may go six weeks and then have to give it up. Because it's not gonna work. For patients who I think can't tolerate waiting four to six weeks to find out if the drug works, I'll usually start quetiopine.

If quetiopine doesn't work, then I'll use clozapine. If the patient is in a really difficult situation where they may need to be hospitalized because they're causing such distress either to themselves or to their family. Then I will start clozapine. [00:07:00] And the trick with clozapine is that you need to start with a very low dose.

So the people with schizophrenia are usually on doses between about 500 and 900 milligrams a day. And for Parkinson's disease patients, I usually start with six and a quarter to 12 and a half milligrams a day. So it's really sometimes a hundredth of the dose of that being used in schizophrenia, and sometimes the response is really remarkable.

You know, patient getting better in one or two nights sometimes. I mean, that's not typical, but it's not uncommon either. It is a pain in the neck to use. I don't want to minimize it. It's not so much that the blood test needs to be done, but the result of the blood test has to be communicated to the pharmacy and patients only get enough drug to get them to their next blood test.

And then if the fax doesn't get received by the pharmacy. They don't give the drug and weather can be bad [00:08:00] and interfere. There are problems, but it still is a much more effective drug than the others.

[00:08:05] Dr. Michele Matarazzo: I think we have already some very important take home messages, so you have this, kind of a algorithm where for mild symptoms you would start with other antipsychotics or other drugs such as pimavanserin or quetiopine, whether they work or not. And then if not, you go to clozapine. And if you have severe symptoms, you go directly to clozapine. That's very helpful from a clinical take-home message. Obviously every patient is different and you have to personalize the treatment. But as a general rule, that seems pretty reasonable and pretty easy.

Now let's change the scenario and go to someone With a lot of tremor, you start levodopa and you increase the dose. All of the symptoms get better, but the resting tremor, it stays there. In which occasions would you consider using clozapine?

[00:08:50] Dr. Joseph Friedman: If the tremor bothers them enough that they're willing to have a weekly blood test for the first six months, I'm willing to use clozapine. Usually I'll start with amantadine. [00:09:00] But as you know, a lot of patients can't tolerate amantadine cause there's a very high incidence of hallucinations with that.

But my usual practice would be to use levodopa, if that didn't work, give them amantadine if they could tolerate it. And if that didn't work, then I use clozapine.

[00:09:17] Dr. Michele Matarazzo: Would you use that before, consider more advanced options such as DBS or a focused ultrasound.

[00:09:24] Dr. Joseph Friedman: Well, yes, I'll mention it to patients that at this point I would recommend clozapine, but that if they didn't want to take clozapine, if they found the weekly blood test or going to the pharmacy every week a problem, then there are surgical options. I mean, in my own mind, being a neurologist, I think of brain surgery as the last resort when nothing else works.

And I figure, as I point out to the patients, they can always try the clozapine. And if they don't like it, if it makes them too tired, for example, or there's difficulty with the blood testing then they could choose a [00:10:00] surgical option.

[00:10:01] Dr. Michele Matarazzo: Now, I will confess, I don't have a lot of experience with clozapine in PD tremor. I've used in few patients. But what would you say is the rate of response? How many patients have a reasonably good response?

[00:10:13] Dr. Joseph Friedman: I think the, a reasonably good response is probably more than half.

[00:10:18] Dr. Michele Matarazzo: More than half. Okay.

[00:10:19] Dr. Joseph Friedman: Maybe not a lot more. You know, it's hard to say because it really is a rather sedating drug, and so patients often can't tolerate it. The anti tremor effect of clozapine requires a higher dose than the antipsychotic effect.

[00:10:36] Dr. Michele Matarazzo: Okay. 

[00:10:37] Dr. Joseph Friedman: Who knows why? Nobody knows why this drug works.

[00:10:40] Dr. Michele Matarazzo: Of course. 

[00:10:41] Dr. Joseph Friedman: But patients may not be able to tolerate 50 milligrams a day or even 100 milligrams a day, which is rarely needed for treating psychosis.

[00:10:49] Dr. Michele Matarazzo: And now let's go to the last scenario. Is there any possibility that you would use the view you would indicate and prescribe clozapine just because of dyskinesia, or maybe you will [00:11:00] consider dyskinesia, between the clinical characteristic that will make you think about using clozapine.

But I mean, just using it because you want to treat dyskinesia in a patient.

[00:11:08] Dr. Joseph Friedman: Yeah, I would not do that. And the reason for that is that the doses required for treating dyskinesia are, much higher even than for treating tremor. And in the two papers that I'm familiar with by Dr. Bennett that were written a long time ago the clozapine was fairly effective for dyskinesias, but patients slept an extra two hours a day on average, and I'm sure there are some patients who slept an extra four hours a day, so that's not a good solution.

[00:11:38] Dr. Michele Matarazzo: Okay. That's another very important take home message. Now I think that I have the last scenario. We have a patient with Parkinson's disease psychosis. We give him or her clozapine, things get much better, but we have the blood count and we see a drop in the neutrophils. What should we do in those cases?

[00:11:56] Dr. Joseph Friedman: Well, obviously you need to stop it because you don't want to kill the patient, [00:12:00] so once you stop it, you can re-challenge them. And I don't have numbers for how often the re-challenge is successful, but it's often successful and sometimes you even have to stop it more than once, two or three times.

However, even if you have agranulocytosis, which you won't get if you do the blood test the way they're supposed to be done. Colony stimulating factor works quite well. So I had a patient who wouldn't go to the laboratory. And actually I reported it because he developed absolute agranulocytosis.

Zero zero granulocytes.

[00:12:34] Dr. Michele Matarazzo: That's scary.

[00:12:35] Dr. Joseph Friedman: Within a few weeks, I think it was eight weeks, but when his blood count started to drop, we told him to stop the drug, which he did, but he wouldn't go to the laboratory. And then it went down to zero and the oncologist really wasn't very concerned, the hematologist. He said, oh, you just put him on antibiotics.

I'll see him in a few days, and gave him colony stimulating factor three to four days later, and within a day or two his white count went up. And I [00:13:00] have a patient who's had recurrent granulocytopenia. And after it happened, I think the fourth time I got the hematologist just to give her the colony stimulating factor, it comes out to about once every four weeks.

So her granulocytes go up to something like 12,000 and then they slowly drop over the next four weeks and she gets another injection. And there are other reports of that. So I think that's probably a very expensive way to go, but it's been very helpful to her because without it, she just has difficult psychotic symptoms.

[00:13:34] Dr. Michele Matarazzo: And I think you just pointed out another very important point, which is that, this first patient you were mentioning with the agranulocytosis, he was missed in the follow up. So, Probably also the having a supportive family or someone around the patient is, very much important when you're choosing a drug like this in which the follow up, especially the lab follow up, is very important, right?

[00:13:57] Dr. Joseph Friedman: Yes. Well, but the thing is because the [00:14:00] rules are that you get only enough drug for your next blood test, that if you don't show up for the blood test, you run out of drug and the natural history of the blood count is that it comes back to normal when you're off the drug.

[00:14:13] Dr. Michele Matarazzo: Great!

[00:14:13] Dr. Joseph Friedman: I guess except if you go to zero, maybe.

[00:14:16] Dr. Michele Matarazzo: Now, is there anything else that you want to share with our listeners?

[00:14:20] Dr. Joseph Friedman: I just think that the doctors who listen to this, who presumably are interested in treating psychotic symptoms and Parkinson's disease should consider using clozapine. I think it's a grossly underused drug, at least in the United States. And I think our patients are suffering as a result of this. 

[00:14:37] Dr. Michele Matarazzo: Well, thank you very much. We have had Joseph Friedman from the Department of Neurology at Warren Alpert Medical School of Brown University, Rhode Island, and we have discussed the article Clozapine is Severely Underused in Parkinson's Disease Patients from the Movement Disorder Clinical Practice.

Please go ahead and download the article from the website and thank you all for listening.

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