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Understanding the Burden and Management of Hallucinations and Delusions Associated With Parkinson's Disease Psychosis

Understanding the Burden and Management of Hallucinations and Delusions Associated With Parkinson's Disease Psychosis

Ask the Presenter

Editors from The American Journal of Managed Care® interviewed
Dr Kremens to gain additional insight on the impact of PDP.
Q & A With Daniel E. Kremens, MD, JD

AJMC®: How do you see the standard of care evolving for patients with hallucinations and delusions associated with PDP as a result of the approval of NUPLAZID™ (pimavanserin), and why?

Dr Kremens: We should hopefully see a paradigm shift in the treatment of hallucinations and delusions associated with PDP as a result of the approval of NUPLAZID. Until now, we’ve been in a Hobson’s choice of treating PDP because atypical antipsychotics tend to block dopamine, but PD patients don’t have enough dopamine; therefore, if we attempt to treat their psychosis, we end up worsening their motor function. NUPLAZID does not interfere with the motor function of patients. Now, with NUPLAZID, we’ll be able to treat the psychosis associated with PD without worsening the motor function.

AJMC®: What are the risks that can lead a patient with PD to develop PDP?

Dr Kremens: A number of risks, both intrinsic and extrinsic factors, can lead to the development of psychosis in patients with PD. On the intrinsic side, comorbid medical and psychiatric conditions are associated with developing PDP. In addition, the PD itself has elements that are risk factors, including the severity of the underlying disease, the duration of the disease, and the fact that older patients tend to be at greater risk for developing PDP. In addition, the underlying neurodegenerative process in PD is implicated in the development of PDP. In PD, there is a loss of various neurotransmitters. Typically, we think of dopamine, but other neurotransmitters are altered in PD; a growing body of evidence suggests that serotonin plays a significant, or even primary, role in the development of PDP. We know that there is loss of serotonin in PD but increased activity at serotonin receptors, and it is thought that this may be one of the reasons why we see PDP.
Another intrinsic factor is visual processing deficit; people with PD have issues with lower visual acuity and contrast. In addition, there are extrinsic factors. Even though we believe serotonin may be the main neurotransmitter involved in PDP, it’s not the only neurotransmitter. Dopamine likely does play a role, and in some patients, the dopaminergic medicine that we use to treat PD may worsen PDP. In addition, there are medicines for conditions other than PD that can worsen PDP, such as anticholinergics that are used to treat medical conditions such as urinary incontinence. And environmental factors, such as dim lighting, can contribute to visual hallucinations.

AJMC®: How likely is it for a patient with PD to develop psychosis?

Dr Kremens: Probably greater than 50% of patients with PD will experience PDP at some time during the course of their disease.2

AJMC®: What symptoms point to the likelihood of a patient with PD being diagnosed with PDP?

Dr Kremens: The main symptoms in PDP are hallucinations and delusions. Hallucinations are the perception of a stimulus in the absence of a physical stimulus. Typically, in PDP, it’s a visual hallucination, but the hallucinations are not exclusively visual; they can be tactile, gustatory, or auditory. There are so-called minor hallucinations, which include illusions, which are a misperception of a physical stimulus. A classic one is if someone throws a belt or a tie on their bed and they see a snake. In addition, there are delusions, which are false fixed beliefs in the presence of evidence to the contrary. The most common that we see in PDP are delusions of spousal infidelity. Often with male patients, they believe their wife is engaging in sexual relationships with others. Also, delusions of persecution are not uncommon; for example, people believe that someone is trying to steal their money. So, the main symptoms are hallucinations and delusions, in the absence of any other underlying condition that could cause them, such as delirium, an infection, or another underlying psychiatric condition, such as schizophrenia.

AJMC®: When do symptoms of PDP begin in patients with PD, and what triggers the initiation of pharmacologic treatment?

Dr Kremens: PDP can occur at any point in the disease, although it’s typically associated with later disease. However, a recent study suggested that a large number of patients may experience some minor hallucinations before they’re even diagnosed with disease, as a sort of pre-motor symptom of PD, such as an illusion, where there is a misperception in the presence of a physical stimulus. But, in general, PDP tends to occur with longer duration of disease.31

When we decide to treat PDP is an interesting question, as well. I think that has to be a discussion between the physician, the patient, and the caregiver. Early in the course of PDP, hallucinations may not be terribly distressing to the patient; for example, the patient may see a small child or animals that aren’t there. Nonetheless, this may be quite distressing to the caregiver, who sees the patient interacting or speaking to people who aren’t there; that can be socially isolating and disturbing. Even though the patient may not be especially bothered, if it’s sufficiently distressing to the family and isolating to the patient, you may want to consider beginning treatment at that time. Certainly when hallucinations or delusions are distressing to the patient, it’s really important to begin treatment. Another point to keep in mind is that even so-called benign hallucinations are generally harbingers of bad things to come, so it’s important to at least begin a discussion.

AJMC®: How likely is it that a patient with PD will need to be hospitalized or institutionalized in a long-term care setting because of PDP?

Dr Kremens: PDP is a significant risk factor for both hospitalization and institutionalization of PD patients. One study suggested that 24% of all hospital admissions of PD patients were for PDP.27 Patients who are admitted to the hospital with PDP are 2.5 times more likely to end up in nursing homes, and nursing homes are associated with an increased risk of mortality.22-24 One study suggested a mortality rate of 40% after 10 years of follow-up in patients with PDP.26

AJMC®: How are caregivers affected by caring for patients with PDP?

Dr Kremens: There is a tremendous burden on caregivers. A study showed that over 40% of caregivers reported declines in their physical health, 65% reported that their close relationships suffered, and nearly half (47%) have increased scores on depression scales.25 The inability to care for a patient who becomes delusional or has disturbing hallucinations often leads to nursing home placement.22

AJMC®: How would you describe the mechanism of action of NUPLAZID, which is a selective serotonin inverse agonist?

Dr Kremens: NUPLAZID is a selective serotonin inverse agonist. To understand this, you have to understand how receptors in the brain work. Many receptors in the brain are capable of initiating signals even when they are not being stimulated, even when you don’t have an agonist bound to that receptor. Signaling can occur without an agonist; that is called basal activity. If you have an agonist, that stimulates a receptor and increases the activity of that receptor. Then there are drugs called antagonists. Antagonists block the agonist, but they permit the ongoing basal activity. Then you have inverse agonists. Inverse agonists suppress basal activity. So, with NUPLAZID, you are suppressing the basal activity of some serotonin receptors in the brain. It’s thought that the effect of NUPLAZID is a result of a combination of an inverse agonist and antagonist activity at serotonin receptors.

AJMC®: What role do primary care physicians, neurologists, and psychiatrists play in the care of patients with PDP?

Dr Kremens: Primary care physicians, neurologists, and psychiatrists all can play a role in the care of patients with PDP. The key thing for primary care physicians and, to a lesser extent, neurologists and psychiatrists is first to recognize PDP. We do a pretty poor job of identifying patients with PDP. The patients themselves often are embarrassed by their symptoms. They’re concerned that if they report that they’re seeing things, someone is going to call them crazy and they’re going to get locked up. So, patients don’t share the fact that they’re having psychotic symptoms. In one study, symptoms weren’t disclosed to the physicians by 41.5% of patients who were experiencing hallucinations and 65.2% of patients experiencing delusions, but then they later reported it in an anonymous survey.19

Primary care physicians and neurologists may be so focused on the motor symptoms of PD that they don’t get around, by the time the visit has ended, to asking about nonmotor symptoms such as PDP. Physicians need to ask patients if they are experiencing hallucinations or delusions, and they need to do it in a way that’s not threatening and not judgmental. Once PDP has been identified, make sure there are no extrinsic factors, such as a urinary tract infection and the addition of an anticholinergic medicine, that might be causing psychosis. When PDP has been established, the primary care physician should get that patient into a neurologist, particularly a movement disorder specialist, or a psychiatrist, someone who has special training in the treatment of psychosis, to better manage the patient. 

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. NUPLAZID is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson’s disease psychosis.
QT Interval Prolongation: NUPLAZID prolongs the QT interval. The use of NUPLAZID should be avoided in patients with known QT pro-longation or in combination with other drugs known to prolong QT interval including Class 1A antiarrhythmics or Class 3 antiarrhythmics, certain antipsychotic medications, and certain antibiotics. NUPLAZID should also be avoided in patients with a history of cardiac arrhyth-mias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death, includ-ing symptomatic bradycardia, hypokalemia or hypomagnesemia, and presence of congenital prolongation of the QT interval. 

Adverse Reactions: The most common adverse reactions (≥2% for NUPLAZID and greater than placebo) were peripheral edema (7% vs 2%), nausea (7% vs 4%), confusional state (6% vs 3%), hallucination (5% vs 3%), constipation (4% vs 3%), and gait disturbance (2% vs <1%).
Drug Interactions: Strong CYP3A4 inhibitors (eg, ketoconazole) increase NUPLAZID concentrations. Reduce the NUPLAZID dose by one-half. Strong CYP3A4 inducers may reduce NUPLAZID exposure, monitor for reduced efficacy. Increase in NUPLAZID dosage may be needed.
Renal Impairment: No dosage adjustment for NUPLAZID is needed in patients with mild to moderate renal impairment. Use of NUPLAZID is not recommended in patients with severe renal impairment.
Hepatic Impairment: Use of NUPLAZID is not recommended in patients with hepatic impairment. NUPLAZID has not been evaluated in this patient population. 
Pregnancy: Use of NUPLAZID in pregnant women has not been evalu-ated and should therefore be used in pregnancy only if the potential benefit justifies the potential risk to the mother and fetus. 
Pediatric Use: Safety and efficacy have not been established in pedi-atric patients.
Dosage and Administration: Recommended dose: 34 mg per day, taken orally as two 17-mg tablets once daily, without titration.

NUPLAZID is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s dis-ease psychosis.

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