Download ABOUT PARKINSON”S DISEASE PSYCHOSIS

ABOUT PARKINSON’S DISEASE PSYCHOSIS (PDP)
Disease Overview
Parkinson’s disease is a chronic and progressive neurodegenerative disorder that affects about
one million people in the United States and from four to six million people worldwide. It is the
second most common neurological disorder after Alzheimer’s disease. Parkinson’s disease
involves the death of neurons in a region of the brain that controls movement, creating a shortage
of an important neurotransmitter known as dopamine, thereby rendering patients unable to direct
or control their movements in a normal manner. Parkinson’s disease is characterized by wellknown motor symptoms, including rest tremor, bradykinesia, rigidity, and disturbances of
balance and posture, as well as by non-motor symptoms, including psychosis, depression, sleep
disturbances, compulsive behaviors and dementia. Among these, the onset of psychosis is
considered a particularly poor prognostic sign.
Parkinson’s disease psychosis, or PDP, is a debilitating disorder that develops in up to 60 percent
of patients with Parkinson’s disease. The development of PDP substantially contributes to the
burden of Parkinson’s disease and deeply affects the quality of life of Parkinson’s patients. PDP
is associated with marked increases in caregiver stress and burden, is the single greatest
precipitant of nursing home placement among patients with PD, and results in substantial
morbidity and mortality.
PDP is characterized by the presence of hallucinations and delusions. Hallucinations are most
common and are often visual but may also include somatic or other sensory phenomena.
Initially, hallucinations may involve a sense of presence or passage, and insight is often retained,
but as the condition progresses the hallucinations become more intransigent and delusions
become more prominent. Delusions commonly involve suspicions of spousal infidelity or other
paranoid themes and are often profoundly disturbing and debilitating. PDP therefore represents a
major inflection point in the course of a patient’s disease, which is compounded by the lack of
appropriate therapeutic options.
Current Standard of Care
Currently, there is no FDA-approved therapy for PDP. Traditionally, there are two approaches
which may be applied in the treatment of the condition. First, physicians may attempt to reduce
or withdraw dopaminergic therapy, the principal component for management of motor
symptoms. However, this approach is generally not effective in alleviating PDP and often comes
at the cost of significant worsening of motor function. Therefore, physicians frequently must
resort to off-label use of antipsychotic medications and, in some cases, hospitalization. Due to
their dopamine blocking properties, antipsychotics may counteract the anti-Parkinson’s therapy
thereby worsening motor symptoms. Only clozapine, when given at low doses, has been shown
to be effective without impairing motor function. Use of clozapine, however, is limited because
it may cause a potentially fatal blood disorder called agranulocytosis. Thus stringent blood
monitoring is required. Low-dose clozapine has been approved in Europe, but not in the United
States for treatment of PDP. Other antipsychotics, including seroquel, have been proven
ineffective in blinded studies of PDP patients or have worsened motor function in these
patients. These agents also are associated with a risk for other significant side effects in this
elderly and fragile patient population. All current antipsychotics carry a black-box warning on
their label for use in elderly patients with dementia-related psychosis because of increased
mortality and morbidity. Nevertheless, because there is no alternative, antipsychotics continue
to be widely used in the treatment of PDP, despite a high prevalence of dementia as a comorbid condition in this patient group. Therefore, there is a large unmet medical need for
new therapies that will treat PDP effectively without compromising motor control or incurring
the risks of serious side effects.
NUPLAZID™ (pimavanserin), ACADIA’s proprietary small molecule that is a selective
serotonin inverse agonist preferentially targeting 5-HT2A receptors, is in Phase III development
for the treatment of PDP. Both scientific and clinical evidence support the rationale for use of 5HT2A receptor inverse agonists, such as NUPLAZID, in the treatment of PDP. This receptor is
strongly implicated in psychotic conditions and, specifically, in visual hallucinations in PDP;
selective 5-HT2A inverse agonists are effective in an animal model of PDP; low doses of
clozapine, which block 5-HT2A receptors but not dopamine D2 receptors, are effective in treating
PDP; and PDP studies with NUPLAZID have provided encouraging results.
References
1.
Lee AH, et al.: “Psychosis in Parkinson’s disease without dementia: Common and comorbid with other
non-motor symptoms.” Movement Disorders, 7, 858-863 (2012).
2.
Marras C, et al.: “Antipsychotics and mortality in Parkinsonism.” American Journal of Geriatric Psychiatry, 20,
149-158 (2012).
3.
Starkstein SE, et al.: “The riddle of psychiatric disorders in Parkinson’s disease: from phenomenology to
treatment.” American Journal of Geriatric Psychiatry, 20, 99-103 (2012).
4.
Friedman JH, et al.: “Atypical Drugs in the treatment of Parkinson’s disease.” Journal of Pharmacy Practice, 24,
534-540 (2011).
5.
Goldman JG, et al.: “An updated expert opinion on management and research strategies in Parkinson’s disease
psychosis.” Expert Opinion in Pharmacotherapy, 12, 2009-2024 (2011).
6.
Hasnain M, et al.: “Psychosis in Parkinson’s disease: therapeutic options.” Drugs of Today, 47, 353-367 (2011).
7.
Ballanger, et al.: “Serotonin 2A receptors and visual hallucinations in Parkinson’s disease.” Archives in
Neurology, 67, 416-421 (2010).
8.
Forsaa EB, et al.: “A 12-year population-based study of psychosis in Parkinson disease.” Archives in
Neurology, 67, 996-1001 (2010).
9.
Diedrich NJ, et al.: “Hallucinations in Parkinson’s disease.” Nature Reviews Neurology, 5, 331-342 (2009).
10. Goetz CG, et al.: “Scales to evaluate psychosis in Parkinson’s disease.” Parkinsonism and related disorders,
15S3, S38-S41 (2009).
11. Weiner, et al.: “Psychosis of Parkinson’s disease: serotonin 2A receptor inverse agonists as potential
therapeutics.” Current Opinion in Investigational Drugs, 4, 815-819 (2003).