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.

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http://forum.parkinson.org/forum/viewtopic.php?t=8846

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:

www.ncbi.nlm.nih.gov/pmc/articles/PMC3002611/

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.

Robin


www.ncbi.nlm.nih.gov/pmc/articles/PMC3002611/table/table2-1756285609348902/

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.

Robin

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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 pubmed.gov for this abstact only – available at no charge)

Argyrophilic grain disease

This is research published several years ago from the Mayo Clinic Jacksonville Brain Bank.  I’ve been noticing some neuropathology reports that mention argyrophilic grain disease (AgD).  Usually this is in combination with progressive supranuclear palsy (PSP).  There are no diagnostic criteria for AgD for when someone is alive.  It may be associated with mild cognitive impairment but it seems we aren’t very sure!

The abstract is copied below.

Robin
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Brain Pathology. 2002 Jan;12(1):45-52.

Argyrophilic grain disease: neuropathology, frequency in a dementia brain bank and lack of relationship with apolipoprotein E.

Togo T, Cookson N, Dickson DW.

Abstract
Argyrophilic grain disease (AGD) is a recently recognized disorder whose relationship to dementia as well as genetic or biochemical features remain incompletely characterized in part due to diagnostic difficulties engendered by concomitant pathologies. In the present study, we reviewed a consecutive series of over 300 brains referred for evaluation of dementia for presence of argyrophilic grains (AGs). AGs were found in the hippocampal region and amygdala, and were accompanied by coiled bodies in the underlying white matter and ballooned neurons in the limbic lobe. Ballooned neurons were also found in the limbic lobe in a number of cases of advanced Alzheimer’s disease (AD) that did not have AGs, supporting the lack of diagnostic significance of ballooned neurons confined to limbic lobe. The frequency of AGD in this series of dementia brains was 4.9% and was similar to the frequency in other autopsy series of nondemented cases, supporting the notion that there is no obligatory relationship between AGD and dementia. In the present series, ApoE epsilon4 allele frequency of AGD was dependent on concurrent AD, with AGD cases lacking AD similar to controls and cases with concurrent AD similar to AD. This suggests that AGD is an independent disease process from AD.

PubMed ID#: 11770901  (see pubmed.gov for the abstract only)

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!
Robin

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]