Treating psychosis in PD and use of antipsychotics

This post will interest those dealing with hallucinations or delusions, or those using atypical antipsychotics, such as Seroquel. This contains a nice summary of why antipsychotics are used and which ones are preferred.

This was posted yesterday on the National Parkinson Foundation’s “Ask the Doctor” online forum. I believe it’s an excerpt from a larger publication on treatment of PD. I learned three things. First, “double-blinded trials of quetiapine have been disappointing.” (quetiapine = Seroquel) Second, “odansetron (a rather expensive anti-nausea medication used mainly for patients undergoing chemotherapy)” is a treatment option for psychosis in PD. I’m pretty sure that’s a typo and what is meant is ondansetron or Zofran. Third, the effects of electroconvulsive therapy (ECT) in treating psychosis are short-lived.


Posted by Dr. Hubert H. Fernandez
Posted on 1/30/10

What medications can be used to treat psychosis in Parkinson’s disease?

Just like the management of cognitive decline, prior to starting any treatment, one has to search for urinary tract infections, pneumonia, metabolic derangements, sleep disturbances, brain insults (such as strokes) and social stressors, such as changes in the environment, as possible explanations for hallucinations or delusions. Medications that can alter brain mechanics because of their ability to penetrate the brain’s “iron curtain” (termed the “blood brain barrier”) that is designed to keep away unwanted substances, such as narcotics, hypnotics, antidepressants, and anxiolytics are also common culprits. If psychotic symptoms persist despite the withdrawal of other psychotropic medications, anti-Parkinson’s disease medications may be gradually reduced or, if necessary, discontinued. As mentioned in Module 4, most authorities recommend “peeling off” these medications in the following order: anticholinergic agents, amantadine, monoamine oxidase inhibitors, dopamine agonists, catechol-O-methyltransferase inhibitors, and finally, levodopa. Regular or short acting formulations of levodopa are preferred in patients prone to hallucinations over sustained-release formulations because their pharmacokinetics are more predictable and there is less potential for cumulative side-effects. If psychosis improves, the patient is then maintained on the lowest possible dose of anti- Parkinson’s disease medications. However, if the withdrawal of anti-PD drugs significantly worsens other Parkinson’s disease symptoms or does not control psychosis one must consider the addition of antipsychotic agents.

The choice of an antipsychotic agent is based largely on its ease of use and side effect profile as most antipsychotics have comparable efficacy in improving psychosis. “Atypical” antipsychotics (or newer generation antipsychotics) are generally preferred given the significant risk of motor complications and anticholinergic side effects with older, conventional antipsychotics. The use of an appropriate atypical antipsychotic agent may allow the clinician to control psychosis with fewer motor side effects and, in some cases, without the need for significantly cutting back on anti- Parkinson’s disease medications. Clinicians should be aware that the FDA issued a “black box” warning for the use of these agents in the treatment of psychosis associated with dementia due to increased cardiac mortality. However, the majority of clinicians treating these patients continue to use these medications because these medications are efficacious, the absolute risk of increased mortality is low and the risk appears to be present in the older antipsychotics as well.

The main difference in the antipsychotics lies in their propensity to worsen motor functioning in this frail and already vulnerable population. Quetiapine has been studied in Parkinson’s disease patients and appears to have less potential for worsening motor function than risperidone, aripiprazole, olanzapine and ziprasidone. While double-blinded trials of quetiapine have been disappointing, it remains the first-line agent used for drug-induced psychosis in Parkinson’s due to its tolerability and good track record in several open-label trials .

The use of clozapine is generally limited to patients who have failed other agents, despite its superior efficacy over all other antipsychotic drugs, because of its very uncommon risk of agranulocytosis (meaning, sudden drop in white blood cell count—our body’s first defense against ordinary infections). The chances of this complication developing are less than 1%. Nonetheless, in the United States, for the first six months, each patient on clozapine must undergo a weekly white blood cell count and can receive only one week’s supply of the drug at a time. After 6 months the process becomes bi-weekly.

It remains unclear how long antipsychotic medications should be continued once they are initiated. There are some data that show persistence of hallucinations in Parkinson’s disease patients with drug-induced psychosis after its initial occurrence. At the University of Florida, we prospectively followed our own patients with Parkinson’s disease on successful long-term treatment with quetiapine or clozapine to see if they could be successfully weaned off their antipsychotic drugs. The study was aborted after enrollment of only six patients due to an unacceptably high rate of psychosis recurrence (five patients, 83%).

Other treatment options include acetylcholinesterase inhibitors, odansetron (a rather expensive anti-nausea medication used mainly for patients undergoing chemotherapy) and electroconvulsive therapy (ECT). Several open-label studies have found that cholinesterase inhibitors may improve hallucinations and psychosis in Parkinson’s disease subjects. Similarly, an open-label trial with 16 Parkinson’s disease patients showed marked improvements in the areas of visual hallucinations, confusion, and functional impairment with no adverse effects on motor function. This result has yet to be reproduced by other investgators. ECT should be reserved for patients who are unresponsive to, or intolerant of, other treatments, especially if the psychosis is associated with severe depression. In general, ECT’s effects are short-lived, and repeated treatments and/or the help of other medications are required to maintain benefits.

[Robin’s note: I think the open-label trial with 16 PD patients above is a trial with ondansetron. And I think there’s a typo above in the drug’s name: an N is missing. The brand name is Zofran.] [Brand names for some of the antipsychotic medications referred to include:
quetiapine = Seroquel
risperidone = Risperdal
aripiprazole = Abilify
olanzapine = Zyprexa
ziprasidone = Geodon
clozapine = Clozaril ]


Treatment of dysautonomia in PD, MSA, DLB, etc.

This medical journal article provides a good overview of autonomic dysfunction in Parkinson’s Disease, MSA, and DLB.

The non-motor symptoms addressed include:

* orthostatic hypotension:  If you are dealing with OH, I especially recommend you review Box 1, “Nonpharmacological and pharmacological treatment of orthostatic hypotension.”  I’ve copied the box below as best I can.

* supine hypertension:  This is probably the best overview I’ve seen.

* cardiovascular effects of antiparkinsonian drugs

* dysphagia (swallowing problems)

* gastric motor dysfunction (delayed gastric emptying).  Note that the medication “Domperidone speeds up the emptying of the stomach…”  This medication is not available in the US.

* constipation

* bowel dysfunction

* urinary dysfunction.  I had never seen this data before:  “More than 50% of MSA patients suffer from recurrent infections and a significant number (approximately 25%) die of subsequent complications.”

And this is a useful point as well:  “Missclassification of urogenital autonomic dysfunction as benign prostatic hyperplasia has been reported which may increase the risk of unnecessary urological surgery.”

* sexual dysfunction

* sweating abnormalities

I suggest reading only about the symptoms or disorder of interest to you.

Wonderfully, the full article is available online at no charge via the PubMed system:

Therapeutic Advances in Neurological Disorders. 2010 Jan;3(1):53-67.
Treatment of dysautonomia in extrapyramidal disorders.
Ziemssen T, Reichmann H.
ANF Laboratory, Department of Neurology, University Clinic Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.

Again, Box 1 about orthostatic hypotension is copied below.


Box 1. Nonpharmacological and pharmacological treatment of orthostatic hypotension.

Nonpharmacological procedures
* Avoid sudden posture changes, particularly after long periods in supine position or during venodilating conditions (i.e. hot baths).
* Increase of daily salt (3-6 g NaCl) and water (2-3 l) intake.
* Diet low in carbohydrates; increase of meal frequency while meal size should be decreased.
* Isotonic exercise such as swimming, aerobic training, bicycling or walking at moderate level.
* Application of counter manoeuvres such as squatting or ‘derby chair’.
* Wearing of elastic stockings or an elastic suit.
* Raised upper body position during sleeping (15-30 cm).

Pharmacological procedures – Increase of blood volume
* Fludrocortisone initial dose of 0.1-0.2mg/d; up to a max of 1mg/d. Caution: cardiac insufficiency, hypocalcaemia, oedema.
* Erythropoietin 4000 IE s.c. twice a week. Caution: iron substitution; increase in haematocrit; hypertension.
* Desmopressin nasal application via pump spray, particularly indicated in nycturia. Caution: hyponatraemia, hypertension.

Pharmacological procedures – Increase of peripheral vasoconstriction
* Midodrine three times 2.5-10mg/d, up to a max 40mg/d; administration not later than 5 pm. Caution: supine hypertension, pruritus.
* Ephedrine three times 12.5-25mg/d. Caution: tachycardia, tremor, supine hypertension.
* Yohimbine two to three times 8mg/d p.o. Caution: diarrhoea, nervousness, panic attacks.
* Caffeine 250mg (=2 cups of coffee) in the morning. Caution: tachyphylaxia.

[fludrocortisone = Florinef; erythropoietin = EPO; desmopressin nasal spray = Stimate or DDAVP Nasal Spray; midodrine = Proamatine]

Improving diagnostic accuracy of PSP-P

PSP folks –

This article was written by two heroes of the PSP community — David Williams, who is now in Australia, and Andrew Lees, in the UK.

“The aim of this study was to identify particular clinical features (green flags) that may be helpful in differentiating PSP-P from…other disorders.”  PSP-P, the parkinsonism form of PSP (progressive supranuclear palsy), is easily confused with Parkinson’s Disease (PD), multiple system atrophy (MSA), and vascular parkinsonism.  The issue is that the PSP diagnostic criteria include symptoms that are specific to the dementia form of PSP.  But what if someone with PSP-P comes along?

In this study, researchers compared many Queen Square Brain Bank cases:  37 patients with PSP-P, 444 with PD, 46 with dementia with Lewy bodies (DLB), 90 with MSA, and 19 with vascular parkinsonism.

By the way, a total of 127 PSP brains from QSBB were examined.  Of those, 86 had Richardson’s Disease, or the dementia form of PSP, while 37 had PSP-P.  (Four cases must’ve had rare forms of PSP.)  The researchers describe this division as follows:

“PSP cases were further divided according to their clinical features present in the first 2 years of disease. When the clinical notes recorded falls, supranuclear gaze palsy, abnormal vertical saccadic eye movements or cognitive decline within the first 2 years patients they were classified as RD (n = 86). Patients were classified PSP-P when their history included asymmetric bradykinesia, rigidity, a positive L-dopa response or tremor, and the cardinal features of RD were not present (n = 37).”

That breakdown — 29% with PSP-P and 68% with RD — is roughly what we see in our local support group:  most have the dementia form of PSP but about a third have the parkinsonism form.

The authors state:  “The clinical differences between RD and PSP-P are most likely to be due to differences in pathological severity.”  (By the way, an effort is apparently on to rename the dementia form of PSP to “Richardson’s Disease,” or RD, rather than Richardson’s Syndrome.)

Past studies have shown that the diagnostic accuracy for RD is much higher than that for PSP-P: 86% vs. 41%.

After comparing the clinical records, researchers found no clinical features “predictive” of PSP-P.  (No wonder this form of PSP is so hard to diagnose!)

In distinguishing PD, DLB, and PSP-P, three clinical features were found to be most important:  “late drug induced dyskinesias, late autonomic dysfunction, and any visual hallucinations.”  These three symptoms are very uncommon in PSP and “may be helpful exclusion criteria.”  Note that none of these three features is an early symptom.

Researchers also found many features to distinguish MSA and PSP-P:

“Late non-specific eye symptoms and supranuclear gaze palsy were good discriminators of PSP-P. Three other clinical features, when calculated with respect to a diagnosis of MSA, appeared to be reasonable discriminators of MSA, including early autonomic dysfunction, late autonomic dysfunction, and late cerebellar signs, which occurred in more than 50% of MSA patients and less than 10% of PSP-P patients.”

These statements in the Discussion section about differentiating PSP from PD were interesting:

“The nature of bradykinesia has rarely been examined in detail in different diseases, but our impression is that rapid hypokinesia – reduced amplitude of movement, that is, fast and without decay, is more typical in patients with PSP than true bradykinesia typical of PD. Equally, fast micrographia and rapid hypophonia may also be clues to PSP pathology.”

This may be enough for most of you.  The abstract follows.



Movement Disorders. 2010 Jan 27. [Epub ahead of print]

What features improve the accuracy of the clinical diagnosis of progressive supranuclear palsy-parkinsonism (PSP-P)?

Williams DR, Lees AJ.
Van Cleef Roet Centre for Nervous Diseases, Monash University, Melbourne, Victoria, Australia.

Progressive supranuclear palsy-parkinsonism (PSP-P) is a primary tauopathy characterised by neurofibrillary degeneration, which is frequently mistaken for Parkinson’s disease (PD), multiple system atrophy (MSA), and vascular parkinsonism (VP) at presentation. The aim of this study was to identify particular clinical features (green flags) that may be helpful in differentiating PSP-P from these other disorders.

We identified 37 patients with PSP-P from 726 patients archived at the Queen Square Brain Bank. Using a retrospective case notes review the clinical features were compared between the PSP-P group and Lewy body associated parkinsonism (PD, n = 444 and dementia with Lewy bodies (DLB), n = 46), MSA (n = 90), and VP (n = 19), using the chi(2)-test for proportions for a two-by-two contingency table.

The sensitivity, specificity, and positive predictive values (PPV) and negative predictive values (NPV) were calculated for individual clinical features. A specificity of >0.85 or a PPV of >0.85 were considered reliable discriminators.

No clinical features were predictive of PSP-P, but late drug induced dyskinesias (specificity 0.92, PPV 0.99), late autonomic dysfunction (specificity 0.94, PPV 0.99) and any visual hallucinations (specificity 0.94, PPV 0.99) were better in distinguishing PD and PSP-P than predicted using operational diagnostic criteria for PD. PSP-P shares many clinical features with PD and DLB, MSA and VP, but visual hallucinations, drug induced dyskinesias and autonomic dysfunction are very uncommon and may be helpful exclusion criteria.

PubMed ID#: 20108379   (see for this abstact only – available at no charge)

Case Rpt- “Dramatic improvement” with Ambien CR

I don’t get too excited about a report on a single case but you be the judge!

Journal of Clinical Neuroscience. 2010 Jan 11. [Epub ahead of print]

The use of zolpidem in the treatment of progressive supranuclear palsy.

Cotter C, Armytage T, Crimmins D.
Department of Neurology, Northern Sydney Central Coast Health, Gosford Hospital, Gosford, New South Wales, Australia.

Progressive supranuclear palsy (PSP) is a debilitating progressive neurodegenerative disorder for which there is no proven pharmacological treatment.

Zolpidem immediate release formulation has been reported to show short-term improvements in motor function and voluntary saccadic eye movements, but the benefits were not sustained.

A 61-year-old man with a 4-year history of PSP was observed over 6 months to have sustained improvement in motor function, pseudobulbar symptoms and ocular motility 2 months after commencing zolpidem controlled release (CR) formulation. He was admitted to hospital and a detailed neurological and functional assessment recorded on video after withdrawal of zolpidem CR, and again following re-introduction of the medication. Within 1 hour of administration of 25mg zolpidem CR the patient had a dramatic improvement in fine motor skills, dexterity, speed and fluidity of movement, facial and vocal expression, oropharyngeal coordination and function and pursuit, and voluntary saccadic eye movements. These improvements were observed for 4 hours to 5 hours post-dose and were reproducible on subsequent withdrawal and re-challenging. We found that zolpidem CR, a gamma aminobutryic acid (GABA)ergic agonist of the benzodiazepine type 1 receptor, caused sustained improvement in motor and ocular symptoms in a patient with PSP over 6 months.

Further studies are needed to determine the potential roles of GABA neurotransmission in PSP.

PubMed ID#: 20071178

[zolpidem = Ambien; zolpidem CR = Ambien CR]

The Eye in PSP/Atypical Parkinson’s – lecture notes

At last week’s atypical parkinsonsim support group meeting at UC Irvine, a neuro-ophthalmologist spoke about eye problems in parkinsonism. The talk wasn’t specific to PSP, CBD, or MSA. Vera James is the facilitator of this PSP/CBD/MSA support group. Here are Vera’s notes, which she posted to one of the MSA-related online support groups last week.

Orange County Atypical PD+ Support Group (PSP, CBD, MSA)
UC Irvine
Meeting date: Wed, Jan 6, 2010
Notes by: Vera James, support group leader [with a few grammatical fixes by Robin]

Guest speaker: Swaraj Bose, MD, a neuro-ophthalmologist at the Gavin Herbert Eye Institute, UCI

His main reason for speaking with us was to give us a fair idea of the eye problems and why do the eyes behave in the way they do in Parkinson’s/PSP/Atypical Parkinson’s and what the caregiver can do.

The eye movement comes from the brain (head computer). We have two eyeballs that are in an orbit/socket. Each eye has 6 muscle that moves the eye left to right or up and down for the visual field. The vision comes from the back of the brain at the cortex, the middle brain, neurons of the pons. These nerve cells and area are what causes the problems.

Dr. Bose gave us a handout called “The Eye in PSP/Atypical Parkinson’s.” The information will all be in this message along with some notes I made when he made remark about some of the common things in Parkinson’s/ PSP/Atypical Parkinson’s. Some information is vision problems in PSP like the down-gaze that is common with PSP patients but some suggestion you may find will help the MSA patients also. I am also putting those in because we know that some patients may be misdiagnosef and may have these same eye issues.

Common eye complaints:

#1 – Related to disturbance of down-gaze PSP.

– Difficulty in coordinating eye movements while reading even if their vision is normal, especially through their bifocal glasses.

– Difficulty in eating because they cannot look down at their food on the plate.

– Difficulty in going downstairs and stepping off curbs.

#2 – Related to lack of convergence/fast and slow tracking- Parkinson/PSP/Atypical PD.
(Note: Convergence means to bring the eyes together)

– Difficulty in focusing, words run into each other.

– Hard to shift down to the beginning of the next line automatically after reaching the end of the first line.

– Inability to quickly move eyes up or down.

– Inability to track moving objects or maintain eye contact.

Dr. Bose said that most patients with any of these illnesses will have problems maintaining eye contact, and in tracking objects. He said this is where the problem comes in with driving and the reason that a patient shouldn’t be driving. He gave an example saying that if you are driving and a child run out in front of you 150 ft away, you will catch them going the one way, but with the slow tracking the eyes are doing, the child could be back in front of you before your tracking would get the eyes to the other side to view where the child would be. By then you could have hit the child.

– Double vision.

One eye sees one thing, the other eye sees another and the brain brings them together. Kind of the way 3D glasses do. When you have double vision, the brain isn’t bringing the eyes together to get the one vision.

#3 – Related to vision disturbances-Parkinson/PSP/Atypical PD.

– Difficulty in focusing/blurry vision/visual hallucinations.

Visual hallucinations can be in all of these illness. Some visual hallucinations can be from to much medication, but it can also be from a lack of dopamine in the cortex where the signal is fallen and gives false images and causes these visual hallucinations also. So not all visual hallucinations are psychotic. Other things that can also cause visual hallucinations are benadryl and OTC cold meds. They can also cause spasm.

– Changes of reading glasses at a quicker intervals.

– Decreased in contrast sensitivity (difficulty in distinguishing shades of gray) and color perception.

#4 – Eyelid abnormality

– Difficulty in voluntarily opening their eyes (apraxia)

– Forceful eyelid closing (blepharospasm). This is treated with botox.

– Decrease in the rate of blinking (3-4/min vs. 20/min)

#5 – Dry eyes

– Burning sensation, redness, watering, itching, excessive tearing, rubbing of eyes, blurry vision.

– Double vision with one eye. Usually results in ‘ghosting’ of images or shadowing of images.

Treatment — A multi-disciplinary approach:

Diagnosis of the movement disorder is important. This will determine the course, manifestations and outcome.

Communication with neurologist, neuro-ophthalmologist, rehabilitation personnel, nurses, therapists, care giver, neuro-psychiatrists amd primary care physicians is VITAL.

Record a thorough history.

Set realistic goals.

A thorough eye examination should include:
– Best correction for distance/near vision
– Color vision
– Visual field examination
– Detailed record of eye movements in all directions
– Prism measurement and correction. Prism lenses or prism overlays take some getting used to.
– Evaluation of eye surface including dry eyes
– Eyelid evaluation
– Convergence estimation.
– Retina and optic nerve evaluation
– Prescribe glasses for distance and near
– Optimize eye movement problems by exercises, prisms and rehabilitation
– Treat dry eyes and other associated eye conditions

Alter/Redesign equipment for reading (lighting, position), position of book and food (at eye level), devices/support for walking and stepping down stairs to prevent falls (safety).

Take medication regularly and watch for side effects.

Living and seeing well:

Safety begins at home:
– Rooms/hallways free of clutter
– Remove cords/rugs from floor
– All rooms well lit, night lights along hallways
– Install grab bars in shower, stairs to prevent falls
– Cane, walker, wheel chair

Proper reading lights (from left and behind)

Reading material (books/newspapers) at eye level. Use a piano reading stand.

Place food at patient’s eye level, raise table, small platform. Suggestion: bed or TV tray placed on the table to raise the plate higher for the PSP patient to view food. This would also be helpful for all patients who are still feeding themselves so they don’t have to work as hard to bring the food up to their mouths.

Get correct glasses prescription filled

Use separate glasses for reading and distance

Use lubricating eye drops like Systane or Refresh during the day and a gel (Genteal gel ointment) at bed time.

Regular eye exercises (when prescribed). Body and breathing exercises.

Take medications regularly

Visual hallucinations can be a side effect of medications or a lack of dopamine in the cortex.

Driving can be tricky. Speak with your eye doctor.

Keep yourself engaged with some creative activities/projects

Regular follow-up with neurologist and neuro-ophthalmologist

Join a support group


* Visual disturbances and eye changes including problems with eye movements are commonly seen in patients with Parkinson’s/PSP/Atypical Parkinson’s

* Visual complaints are usually distortion or blurry vision, near vision problems, color vision abnormalities and even visual hallucinations

* Eye movement abnormalities include difficulty in convergence (bringing the eyes together while reading), lack of vertical movement of eyes (upward/downward gaze abnormality) and eye movement asymmetry

* Other problems include a decrease in blinking of eyelids, difficulty in opening the eyelids, dry eyes and lack of facial expression

* These eye conditions, if diagnosed early in the course of the disease, can be treated and managed by an ophthalmologist or a neuro-ophthalmologist

* Simple measures used in visual rehabilitation and medications given by the movement disorders neurologist and supportive care can significantly alter the quality of life of patients with these conditions.