As many as 1 million Americans experience symptoms of Parkinson’s Disease with many ultimately suffering the complications of hallucinations and delusions.  Early manifestations of Parkinson’s Disease generally include a resting tremor principally affecting the hands and remarkably occurring in the absence of other body activity. This shakiness tends to disappear during body movement.  As this progressive disease worsens an overall slowness interferes with walking and leads to characteristic rigidity.  Other complicating factors with varying frequency include excessive saliva, drooling, sleep disruption, depression and constipation.

Recently advertisements in the guise of public service messages focus attention on the relatively neglected accompaniments of this condition: hallucinations and delusions.  These tend to occur relatively late in the disease generally developing many years after the original diagnosis.  These symptoms often represent the natural progression of the disease but at times result as complications of therapy aimed at controlling the motor abnormalities.  Hallucinations and delusions ultimately affect as many as 50% of individuals suffering Parkinson’s Disease.

Hallucinations and delusions fit into the category of Parkinson’s Disease Psychosis.  Their sudden appearance often startles patients unless otherwise forewarned.  Due to embarrassment, self-doubt and  questions about their sanity, many patients suffer in silence and fail to disclose these troubling events to either health care provider or spouse.

Difficulty coping with this added burden may extract a dramatic toll on family members and caregivers at times precipitating nursing home placement which propels the disease trajectory onto a downward spiral unfortunately often terminating in premature demise.


Hallucinations represent false sensory experiences.  They may involve sight, sound, smell, feel or taste.  Most prevalent among hallucinations are sensing animals or people, either living or dead, but not actually present.  Unlike nightmares, Parkinson’s Disease related hallucinations tend to be neutral or benign in tone.  Somewhat less frequently people incorrectly believe they hear voices or music.  Abnormalities involving smell, touch and taste rarely cause problems.


Delusions equate to false beliefs persisting is spite of firm evidence indicating the thoughts are incorrect.  Examples include fears that a loved one is stealing the patient’s financial assets or that the spouse is unfaithful.  Some people suffer delusions related to jealousy, persecution or personal grandeur.  While delusions appear less frequently than hallucinations, their presence indicates more advanced disease and augers a more progressive course.

Of course hallucinations and delusions associated with Parkinson’s Disease must be differentiated from psychotic manifestations related to other medical and psychiatric disorders.  Generally affecting an elderly population, Parkinson’s Disease occurs in a relatively fragile population susceptible to depression, adverse reactions to drug therapy, delirium and at times schizophrenia-like conditions.


Our current understanding of Parkinson’s Disease suggests it represents loss of the brain cells located in the substantia nigra that are charged with manufacturing dopamine.  Treatment for the movement portion of the disease usually involves medication to boost levels of this important neurotransmitter.  Sinemet combines levodopa with a chemical that delays its metabolism.  Unfortunately this appears to hasten the onset of hallucinations and delusions or at least magnify their manifestations.


This creates quite a dilemma:  either reduce the dose of Sinemet and allow the motor abnormalities to worsen or add an FDA approved anti-psychotic drug that interferes with activity of dopamine.  Further complicating the situation, the available so-called atypical anti-psychotic drugs Seroquel and Clozapine, while FDA approved, have not been specifically vetted for use in Parkinson’s Disease related hallucinations and delusions.


In spite of the in limbo status of these drugs, the American Academy of Neurology recommends Clozapine as a first choice and Seroquel as an alternative.  However rather severe complications especially associated with Clozapine cause hesitation among the medical profession.  Both drugs impair dopamine activity and may further exacerbate the underlying movement abnormality.


Into this void comes a recently approved medicine Nuplazid known generically as pimavanserin.  In order to create awareness and generate interest, the drug manufacturer Acadia Pharmaceuticals sponsors frequently appearing advertisements that refer interested parties to a website: moretoparkinsons.com.  Presently the site provides information about hallucinations and delusions associated with Parkinson’s Disease without even mentioning a specific form of therapy.  Assuredly that will change in the near future.

Approved by the FDA in April 2016, Nuplazid received the indication specifically for the hallucinations and delusions associated with Parkinson’s Disease.  Perhaps even more promising this drug, while an atypical anti-psychotic similar to other drugs in the family, does not interact with dopamine centers in the brain.  This fact allows prescription of Nuplazid without the fear of worsening the underlying movement disorder or the necessity of reducing the dose of Sinemet.


Actually the FDA bestowed on Nuplazid the very impressive distinction of “breakthrough status” while granting it priority review.  But the FDA hastens to correct any false implication by the common meaning of the terms.  Breakthrough status simply means that a drug, in this instance Nuplazid, potentially offers an improvement in treatment, safety or effectiveness for a serious medical disorder compared to currently approved therapy.  While the drug under consideration must provide at least preliminary evidence that it may be beneficial, the FDA provides no assertions regarding the eventual merit or ultimate success of the compound.


Surprisingly the medical evidence behind Nuplazid appears rather weak.  Not only did the drug company Acadia actually fund many of the studies but it also provided financial support to many of the researchers.  Additionally several of the authors of medical articles championing the merits of the drug were employed by the pharmaceutical company.  These issues elicit concern regarding potential bias and accuracy of their conclusions.


So what is the evidence?  Well the major study persuading the FDA to authorize its sales lasted only 6 weeks and included 89 patients who received a placebo while only 87 were treated with Nuplazid.  Actually the treatment group originally encompassed 105 people but was winnowed down to a much smaller number for a variety of reasons.  Overall hallucinations and delusions improved in 14% of individuals treated with a placebo compared to 37% on Nuplazid.  While this appears statistically significant, the meaning appears clouded.

The 37% figure actually references an improvement in the rating score the company seems to have been involved in creating.  Known as the Scale for the Assessment of Positive Symptoms – Parkinson’s Disease, this 9 item scale rates symptoms of Parkinson’s Disease associated hallucinations and delusions.  Patient scores improved with the drug from about 16 at baseline to 10 at the end of the trial.  For placebo recipients the score went from about 15 to 12.  In neither case were symptoms extinguished.  Perhaps more interestingly when evaluated separately, neither the hallucinations nor the delusions were significantly different between drug and placebo.

Additionally about one quarter of patients treated with Nuplazid worsened or showed no improvement on therapy.  According to the report that appeared in The Lancet, a British medical journal, 11% of the Nuplazid group suffered a serious adverse event compared to only 4% with a placebo.  Some of these side effects included swelling of the legs, feet and ankles, confusion and even hallucinations.


Of course all drugs may cause side effects and Nuplazid as an atypical anti-psychotic certainly seems linked to a moderate number of potentially devastating problems.  As with all drugs in this class, the FDA requires a specific warning that atypical anti-psychotics have been associated with an increased risk of death when prescribed to patients with dementia related psychosis.  And Parkinson’s Disease remains a well established contributor to dementia.  The FDA warns Nuplazid has no role in treating aggression, agitation or other behavioral abnormalities.

For people with an certain abnormality on their electrocardiogram or a history of cardiac arrhythmia, Nuplazid may lead to very severe and potentially life threatening ventricular rhythm disturbances or even sudden death.  The incidence peaks when combined with the drug amiodarone, certain commonly prescribed antibiotics and low levels of either potassium or magnesium.


According to the paper, patients were recruited from 52 academic medical centers and institutions specializing in neurologic research.  Most were located in the United States with several in Canada.  This wide network of facilities certainly seems way out of proportion for a study involving fewer than 200 patients suffering such an apparently routine complication of an extremely common condition.


Several other studies on the drug failed to provide a statistical improvement compared to placebo.  These investigations used the more common, broader scale, SAPS – Hallucinations + Delusions.  Only when the company changed rating scales to their newly modified and recently created version were  modest benefits detected in a single study.  Another foray by the company required early discontinuation evidently due to some unspecified issue, but apparently the patients symptoms failed to improve.  At this time no completed study exists in the medical literature to assist in determining whether the patients were harmed or perhaps some other unanticipated problem occurred.


As an aside, Acadia firmly believes Nuplazid provides benefits beyond the hallucinations and delusions of Parkinson’s Disease.  They recently evaluated it for the same symptoms associated with Alzheimer’s Disease.  Preliminary results at 6 weeks boosted their enthusiasm and suggested a scintilla of benefit compared to placebo.  Unfortunately the company made the error of following patients for a total of 12 weeks.  By then no statistically significant benefit existed when comparing the active drug against a sugar pill.

It will be interesting to observe whether the scale employed in that study, the NPI-NH Psychosis Score, survives into the next round of testing.  If history repeats itself, perhaps the company’s investigators will consider the need to update that method of evaluating patients to more closely align with their needs as appears to have been the case with the final and so far only successful Parkinson’s Disease project.

None of this seems to deter Acadia from attempting to expand the indications for their primary drug.  The company plans to evaluate this therapy for a variety of dementias including those not only linked to Alzheimer’s Disease and Parkinson’s Disease but also to vascular dementia, frontotemporal dementia and dementia associated with Lewy bodies.  Of course the indication will remain limited to the hallucinations and delusions that often accompany these degenerative brain diseases popularly referred to simply as dementias.


Acadia also seems interested in evaluating Nuplazid as an add-on therapy for patients  inadequately responding to therapy for schizophrenia and major depressive disorder.

Whenever drugs with rather limited or modest effects are aggressively marketed to the general public, financial interests and Wall Street often lurk in the background.  In the case of Nuplazid and Acadia, some estimates suggest potential sales of the drug will exceed $1,500,000,000.00 by 2021.  Evidently the company plans a massive sales pitch to medical professionals in order to gain market share.


So how much does a month worth of therapy with Nuplazid cost.  Right now the average retail cost remains just shy of $3,000.00 for 60 tablets – a month’s supply which translates to about $90 a day.  This equates to well in excess of $30,000.00 a year for a drug that according to some was anticipated to come on the market with a yearly price about half that much.  Of course most expect this astronomical sum will be somewhat diminished by pricing skullduggery and behind the scenes negotiations with insurance companies and pharmacy benefit managers.

Since many of the patients anticipated to receive prescriptions for this drug will be receiving federal assistance or Medicare, the actual funding for the drug appears likely to originate from the public treasury and be transferred to the pharmaceutical company.

Although lacking specific FDA approval for treating hallucinations and delusions associated with Parkinson’s disease, competitors such as Seroquel and Clozapine cost as little as $10-$30 a month.  These drugs, approved for other indications, have been favored by the American Academy of Neurology.  By some accounts Clozapine provides greater benefits than Nuplazid, although the side effect profile creates anxiety in prescribers who generally opt instead for Seroquel.


In summary it appears that Nuplazid offers at best a limited role in treating the hallucinations and delusions associated with Parkinson’s Disease Psychosis.  Unfortunately only about of one third of patients under the best of circumstances demonstrate improvement, a rate only somewhat more favorable than placebo effect.  But examining the component parts separately, neither hallucinations nor delusions differ significantly from the proverbial sugar pill.  And all this for a measly $30,000.00 plus a year.  Worse yet, insurance companies, translated to mean Medicare and Medicaid or simply taxpayers, will probably be stuck with the bill.


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