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Management of Drug Induced Psychosis in Parkinson's Disease: A Kingston Centre Approach
Speaker: Dr Robert Iansek
(Transcript from an audio tape recording at the Fourth Australian Multi-Disciplinary Conference on Parkinson's Disease, Sept 1997)
I thought today I would share with you our experiences with the management of this particular problem. It is a very difficult problem to manage and we've developed, mainly by trial and error, a different approach to try and have our cake and eat it. In other words, can we have reasonable mobility without any of the complications of the medication in relation to psychosis.
Now this problem occurs roughly in about 15% of people with Parkinson's Disease and there's a wide variation of the type of symptoms that people can develop and this is a list of the sort of problems that we've experienced, mainly from the patients that have been admitted to the ward with problems. Hallucinations are very common and people usually see visual things. They might see other people in the room that aren't there or they might see animals or they might see ants or some people have described worms in their food and they just put it to one side while they finish the rest of their meal. Visual hallucinations are very common and they are more likely to happen in situations when there's altered environment like in the afternoon when there's changes in light or at night time when there is a lot of shadows. It's situations which lead to misinterpretation and the precursor might be very vivid dreams or nightmares that people can have which is also induced by the medication.
The other complaint is that of paranoia. A feeling that people are against you or out to get you or something is happening directed against you. One particular case that I remember very vividly was a patient who thought that his wife was unfaithful to him and he would go to extreme examples of preventing her from leaving the bedroom at night, even laying the mattress in front of the door and he would sleep on the mattress in front of the door. Now somebody might consider that not being related to the medication at all, but in fact it was. When the medication was reduced, or when the major tranquilliser was introduced, this behaviour ceased completely and it emphasised to me how subtle these psychiatric or psychotic type symptoms can be in people with Parkinson's and you should always think maybe this behaviour, which is out of context, might be due to the drugs because unless you think of it, it may not occur to you that drugs may be responsible.
Confusion is very common and it's common in the elderly age group and basically it's a misrepresentation of events in relation to self. People misinterpret, for example, visually whether someone is close or further apart or whether a conversation that they are hearing is of relevance to them or not. It alters their sensorium so that they become mixed up in time, also in visual perspective and in what they hear and so they become very mixed up. They might go and hop into the wrong person's bed or they might think that their clothes are located in someone else's locker. They start to become mixed up in their behaviour. This is very common in the ward where it is a new environment for people and it tends to bring out this tendency, but medication is responsible for aggravating and even precipitating this sort of behaviour. We've had a number of people who become hypermanic on levodopa medication. Their mind races at 100 miles an hour, they gamble, they buy things, they do 50 million things at once and if you reduce the medication down, then their mentation slows appropriately. We've had lots of people who have attentional deficits so that they cannot concentrate on any one thing for more than a few seconds; their attention flips from one thing to the other. Some people are born with this sort of tendency and normally they can control it. But under the influence of levodopa medication it just gets out of control completely and for people to participate in our rehabilitation program, which requires focused attention on a particular matter that is of relevance to them, this is inappropriate. And so what we tend to do is reduce the medication down so that they can concentrate and focus their attention and it's very interesting to see how this problem ameliorates or becomes better on changing the medication; reducing the medication down.
We have a number of patients that develop mood fluctuations according to their level of levodopa. So when the levodopa arises in the blood they feel so much better, they feel so much more normal and when it drops they start to feel depressed and miserable and it's interesting that people with dyskinesias sometimes titrate their medication according to their mood because they feel better rather than their mobility, and what happens is that they develop a lot more dyskinesias that they would normally need in the sense because they are titrating the medication according to their feelings, rather than to their mobility. This just gives you a spectrum of the sort of problems that medication can cause, aggravate and produce.
How do these things come about? I'm now going to talk mainly about hallucinations and paranoia rather than the other symptoms that I've described there to you or we don't know, but here's a few possibilities.
When you give levodopa you are increasing neurotransmitter in the brain and there's a lot of transmitters that look like dopamine like adrenalin, noradrenaline and 5HT, so if you're boosting dopamine through one system you are probably also boosting these other transmitters within the brain and these other transmitters, in increased doses, may cause other symptoms like for example, hallucinations. And it's been shown that if you can block the increase or the effect of this neurotransmitter by Ondansetron you can actually dampen down hallucinations tremendously. It does nothing however for the paranoia or for the confusion. So there may be some basis to suggest that we're pushing these drugs a lot higher because we are giving people the building blocks for all these transmitters within the brain, not just dopamine and when you give massive doses of this building block you are forcing these nerve cells to increase their manufacture of this chemical transmitter and it overlaps to these other areas.
The other possibility is that when looking at different brain structures through this increase in transmitters, for example, there's a non-motor part of the basal ganglia and as I mentioned to you it's involved in behaviour, in cognition and in mood regulation in an automatic type sense and perhaps we're influencing this part because this is not as severely affected as the motor part in Parkinson's Disease by these increase in transmitters in that part. Maybe it's just dopamine increased in the non-motor part of the basal ganglia, we're getting "psychic dyskinesia" if you like, perhaps that might be an explanation. These chemicals also project to the limbic structures of the brain which are concerned with the elaboration of emotions and the relationship between emotions and behaviour -- how we behave with particular emotions in particular circumstances and perhaps it's these that are causing these changes.
The other possibility is that we can consider dopamine as a key of a particular shape. In the brain there are actually 5 different keys which look a bit the same but are slightly different. And the ones that control movement are keys 1 and 2, and the ones that control mood and behaviour are keys 3 to 5. Now, we know this because people who have psychotic behaviour like schizophrenia or some other psychosis that involves paranoia, the psychiatrists give drugs which counteract these keys here but unfortunately they overlap with these keys here and sometimes can cause movement disturbance. So maybe this might be a mechanism by which these symptoms occur.
The other thing that happens with Parkinson's Disease, which I didn't mention yesterday, is that people with Parkinson's have difficulty monitoring what their movements might be, what their mood might be, what their behaviour might be and what their emotions might be. They don't have an internal register with which to compare what they are doing with what they actually think they are doing and this has been shown to be the way that schizophrenic patients have auditory hallucinations. That they have difficulty in monitoring words internally and it involves a part of the brain called the supplementary motor area which is the motor cortex that I was talking to you about yesterday. So maybe people with Parkinson's are particularly prone to develop these problems because of this malfunctioning of this particular monitoring part of the brain. I don't know what the answer is but these are some of the possibilities.
Well, this is how we approach this problem at Kingston. All patients are admitted to the ward. You cannot possibly manage this complaint at home. Anything you do in this situation is bound to cause problems. We just don't manage it on an out-patient basis. The patients are admitted to the ward and they are supervised by a psychiatrist and a neurologist as well as our multi disciplinary team. We exclude all alternate causes for these complaints such as infection or some small stroke that might have affected the speech area for instance, and we exclude metabolic causes, but invariably there is nothing else to find. Sometimes urinary tract infection which can be very common, or a chest infection if people have trouble swallowing, can cause confusional state, very, very rarely hallucinatory state, but usually we don't find anything and what we do is we stop the drugs that are the biggest culprits and these are all the dopaminergic agonists; the monoaminoxidase inhibiter B - Selegiline; and the anticholinergics. Now, we can't stop these suddenly, because if you stop the anticholinergics suddenly people will develop an acute confusional state. So we really start to wean them down over a period of a couple of weeks and we only function with levodopa and we do this because levodopa is the least likely to cause these sort of problems and because if we reduce all these drugs then we've got more leeway with which to titrate the levodopa up without causing problems if we need to. So it gives us a bit more flexibility in managing these complaints.
We then introduce the major tranquilliser. Now, we start off, or have been using, Pimozide as first line drug. We have used Remoxipride but this was taken off the market after we tried this on two patients because it caused bone marrow depression and the drug company was worried about causing agranulocytosis like Clozapine, so it was taken off the market. Resperidone we've also used and more recently we've started using Olanzapine. We've never used Clozapine because of the difficulty in accessing that drug and because of the side effects of bone marrow depression but Olanzapine, which has recently been marketed, is very similar to Clozapine in that it does not cause a reduction in mobility and still can eliminate the psychotic symptoms and it does not cause bone marrow depression and so this may well be the drug of choice in the future. We've now used this drug in about 18 patients. What we do is we increase the major tranquilliser until the symptoms stop and this is the worst part of this approach because patients will deteriorate in mobility while this is going on, particularly if we're using these drugs here, and we have to support them over this period of time. Once the neuropsychiatric symptoms are controlled then we push up the levodopa under cover of the major tranquilliser and we try and see if we can get the mobility back, and keeping still at bay, the symptoms -- the psychiatric type symptoms.
Now so far we've analysed this information over a 3 year period where we've tried this approach: 366 patients with Parkinson's Disease were admitted in 3 years to the ward and 52 of these had neuropsychiatric problems. So it's roughly about 15% of people in our hands; 30 were males and 22 were females and the mean age was 75.5 years, a mean disease duration of 8 years.
Now we look at the Mini Mental State (MMS) score, in relation to age we can see that the people that would be considered to have dementia and possibly the ones that were borderline dementia were all quite elderly. Whereas the ones that would be considered to have normal cognition on the MMS were much younger and although I haven't got a slide, we also were able to show that the younger people with normal MMS would have psychotic symptoms induced at much, much higher doses of levodopa of the order of 1300 milligrams a day whereas these group of people would have symptoms induced around about 300 or 400 milligrams of levodopa a day. So that it doesn't matter whether you're older or younger, you can still get the symptoms under the appropriate circumstances and although you're more likely to get them if you have cognitive problems, that doesn't really exclude it.
This just illustrates the severity of the symptoms. Now we added symptoms 1, 2, 3: confusions, paranoia and hallucinations, so 3 is the maximum score. This is averaged over the 52 patients that the symptom score was much lower in the younger age group compared to the older age group and it rose as the age group, became older so that the symptom severity was greater in the elderly age group, as compared to the younger age group, so that people in the younger age group might just have hallucinations at a much higher dose of medication with an intact cognitive state, whereas elderly people would be on much lower doses of medication; they would have confusion and hallucinations and possibly a bit of paranoia and it would come on at a much lower dose of medication.
Now the symptom frequency - this is admissions orange and red is on discharge so this is people with paranoia. There was a drop in the number of paranoia with this particular approach. Hallucinations also dropped from admission to discharge but confusion was much more difficult to manage and although there was an improvement with this approach it wasn't as marked as the one for hallucinations and paranoia. Now, these are the findings for how many symptoms each patient had, so this is again on admission in the orange and red on discharge. So initially we had 4 patients that developed the symptoms after they were admitted, not before they were admitted, so we've got some with no symptoms on admission and this is 1 symptom, 2 symptoms, 3 symptoms; what we see is that we're shifting from multiple symptoms down to 0 symptoms or just 1 symptom after treatment. So it tends to improve people. It doesn't help everybody but there is an improvement overall in this population. The levodopa dosages, because we've got such a large range going from 400 to 500 milligrams up to 2.5 grams of levodopa in this population, it's very difficult to show as a group that you have higher dose on discharge, but there is a trend for there to be slightly higher dosages on discharge of levodopa as compared to admission - but there wasn't that much change.
These are the drugs that we used; Pimozide was used as initial major tranquilliser in 47 patients, Resperidone in 3 and Remoxipride in 2. We had to change the major tranquilliser in 10 patients from Pimozide to Resperidone and vice-a-versa. Usually Pimozide causes a lot of saliva and people develop difficulty with saliva control. It can also slow people down quite a lot, unacceptably and may not control the neuropsychiatric symptoms so that would force a change to this alternate drug. Resperidone tends to sedate a lot, so we might have to change from Resperidone to Pimozide because of the sedative affects and two failed both together. That was before we had Olanzapine.
The side effects are increasing difficulty with mobility, excessive salivation and 12% failed to respond. On discharge, 29 were on Pimozide, 13 on Resperidone and 2 on Remoxipride. The mobility scores that we had available to test failed to show any deterioration. They stayed stable, except that gape velocity which we measured with a stride analyser improved overall in the group.
So overall we've been able to achieve approximately a 71% improvement in the symptom score. If we take into consideration improvement in mobility as well, this total package drops to about 50 to 55%. So in 50 to 55% by this approach we can have our cake and we can eat it as well.
Now I should mention that if you look at even the effects of Clozapine it isn't that much different, particularly when you look at follow up data as well. We followed these patients up for 34 months and 23 remained on the major tranquilliser over that period of time, but over that 34 months there was a gradual drop off in the use of the major tranquilliser. So that by 34 months 19 of the patients had stopped using the major tranquilliser. Sometimes it was just omitted from the medication, presumably they didn't have any problems and the problems didn't re-emerge. Sometimes it was a problem that they had more difficulty with saliva control and so it was ceased and sometimes it was because of mobility. Sometimes there wasn't enough information recorded in the notes to work out why it had been stopped. Over this time Pimozide remains the one that's used more frequently and the 2 patients that were taking Resperidone and Remoxipride have been on that all this time.
There was some requirement to increase the Pimozide on follow up but it was only by a very small amount and the Resperidone remained relatively unchanged. I should mention that the dosages that we use are very, very small. For Pimozide it's usually 1 or 2 milligrams a day at the most and most people drop back to 1 milligram every third day. Some people just take 1 milligram a week. It's got a very long half-life and you're able to do that if they develop lots of problems with slowness of movement. And what we tend to do is we tend to titrate the levodopa with the major tranquilliser up and down a little bit once you've established on this combination. The Webster Score on follow up didn't really change - both the ones on major tranquilliser and the ones not on major tranquilliser were roughly the same.
So in conclusion, I believe that neuropsychiatric symptoms in Parkinson's Disease can be managed. We can have our cake and eat it as well. I think that mobility can be maintained in a proportion of patience. You need a rational approach to management. We need firstly to control the symptoms with the major tranquilliser, we then push the levodopa up to try and regain mobility. We get rid of all the other drugs that are more likely to cause these symptoms and just stick to one dopaminergic drug. It has to be done in an experienced unit that's got the capacity to look after these people and the consequences and problems that can develop. People have to be admitted - you can't do it on an out-patient basis and you need neurological as well as psychiatric supervision.
Now I'm not saying that this is a panacea - it's not. We have some terrible problems on patients on major tranquillisers, but what will happen is that these people will end up in a nursing home and what we're trying to do is to save these people from ending up in a nursing home and I think with the introduction of Olanzapine -- we've still got to analyse our data -- but it's certainly is less likely to produce movement slowing and therefore more likely to help us manage this complaint in the future.
Thank you.
Questions & Answers
Questions Q1: Once the patient is off the agonists and the psychosis disappears, do you lose the motor benefits that the agonists were prescribed for in the first place?
A1: Well, from my experience, I'm not convinced that the dopaminergic agonists are particularly powerful agents and therefore I don't think that in the context of neuropsychiatric symptoms that it's a real issue in a sense because what we're trying to do is maintain a level of mobility without the psychiatric symptoms and the alternative is you reduce all the medication all together and people are immobile and no neuropsychiatric symptoms. So... it's a very difficult problem to manage and given those circumstances I think it's not unreasonable to take drastic measures. It gives us more leeway to manage with levodopa than it does with the dopaminergic agonists. I really don't think Bromocriptine does much to tell you the truth. I mean, it really is not a very powerful agent. Permax maybe in some individuals, but the side effects are terrible... and they are very prone to cause this. Not only that, a lot of people find that their mentation is befuddled - they can't think straight, they are all confused. Even if they don't have neuropsychiatric problems. So I don't have any qualms about stopping the dopaminergic antagonist in these particular situations. You can manage people reasonably well with the variety of levodopa preparations that are available.
Q2: Are the side effects the same with slow release as well as regular medication? A2: Yes.
Q3: Robert, I would just like to make a comment. Western Australia has a bed crisis forever now. I think it's never going to change and I think that your impression was that all these patients go to hospital. I mean, many of these patients can be managed as out-patients unless they have got paranoia or suicidal or disruptive families. People that come along with just visual hallucinations that are pleasant and are not particularly disturbed can be managed as an out-patient and we have to make do because we don't have the beds, so there's a crisis. I mean people with Parkinson's come into our hospital are almost non-existent.
A3: Well I'm fortunate that I work in a geriatric hospital. I don't work in an acute hospital and we're geared towards managing people over longer periods of time. But I can tell you that whenever I have tried to do it on an out-patient basis I get a phone call within 24 hours, "I can't get this person out of bed", "What am I going to do?", "He's wandering in the night", "They're urinating in the corner", "They're all over the place" - I've given up...I admit them. You can't manage it at home. It's far too difficult.
Q3: I do agree with that to a certain extent, but many patients just have visual hallucinations that aren't particularly distressing and of course some in fact are living with their symptoms.
A3: Well the people that do have minor hallucinations you can treat. I mean you might just get away by reducing the medication down a little bit without introducing a major tranquilliser. What I'm saying is that if you have to introduce a major tranquilliser I prefer to put people into hospital because of the consequences. Now Olanzapine may be different but see we've had 3 patients who actually became more confused on Olanzapine and we had to stop it, so I don't necessarily know that that is going to be the panacea either and because we deal predominantly with patients that have had disease for many, many years and they've got complex problems and multiple difficulties, it's so much easier to have them in hospital under very close observation. And even in hospital when you introduce the major tranquilliser they can't move and they need assistance in most activities of daily living. I think it is very unfair on a carer alone, 24 hours a day for them to do that.
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