Hallucinations and delusions are common in Parkinson’s disease (PD) whether or not they are associated with dementia. These psychotic symptoms may cause great concern for patients and caregivers. Hallucinations in PD can occur in any sensory modality and sometimes simultaneously. Up to 40% of patients with PD, the majority under treatment with multiple drugs, report these symptoms. Although the cause of these symptoms is still not completely understood, emerging evidence suggests that they result from the progression of the underlying pathology in multiple brain regions unmasked or exacerbated by PD medications. Drs. Friedman, Pontone, and Juncos are experts in this topic and will discuss the key points in view of recent research advances.
What are common presentations of psychotic symptoms in PD and how do they differ from other disorders?
Dr. Friedman
Hallucinations are far and away the most common of the psychotic symptoms. These are primarily visual, with auditory about half as common and others, primarily tactile, much less. In addition, PD patients often report “presence hallucinations,” which are a feeling of someone or something else present, generally behind or to the side, just out of view. When the patient looks for the person or animal, there is nothing there. These are not truly hallucinations, but we use that terminology anyway. “Passage hallucination” is the term used for visual hallucinations, which occur in the peripheral visual field. They are usually shadows or cats or dogs passing by, but when the person looks at them, the images disappear. The “major” hallucinations, are typically visual, of non-threatening people or animals, ignoring the patient. They tend to recur, and usually are the same image each time. Auditory hallucinations tend to be a bit different, music coming from a different room, the radio playing, people talking in the corridor but cannot be understood. Tactile hallucinations are usually the sense of a small animal or insect crawling on the skin. They are usually annoying but not so bothersome as they sound. Olfactory and gustatory hallucinations are rare.
Delusions, false, irrational beliefs not based on real data, are generally paranoid, with feeling of spousal infidelity, thoughts that caretakers are stealing or misplacing objects on purpose, or that the patient is to be institutionalized. In primary psychiatric disorders, like schizophrenia or severe depression with psychosis, the hallucinations are generally auditory and have significant emotional importance, saying bad and denigrating things when the patient feels poorly about himself, or wonderful things if he has delusions of grandeur.
Dr. Pontone
Historically, schizophrenia is held to be the quintessential example of a psychotic disorder. Symptoms most often include auditory hallucinations, hearing several voices talking about or to the afflicted and delusional thoughts, which are false, fixed, idiosyncratic beliefs. Disorganized speech and behavior are also symptoms of schizophrenia. In addition to these “positive symptoms”, schizophrenics can have “negative symptoms” such as neglect of personal duties like hygiene, socialization, and may even lack the motivation to participate in everyday activities. Together these symptoms cause a distressing psychiatric syndrome, which results in a “downward spiral” with decreasing ability to function in daily life and increasing difficulty differentiating hallucinatory experiences from reality.
Psychosis in PD differs from schizophrenia at both the level of the symptom and syndrome. For example, auditory hallucinations are much more common than visual hallucinations in schizophrenia, while the reverse is true in PD. Similarly, delusions occur in almost all persons affected by schizophrenia, but are present only in a minority of persons with PD. In addition to quantitative differences in which sensory modality is affected and how frequently delusions occur, there may also be qualitative differences in how the symptoms are experienced such as greater preservation of insight in PD psychosis, e.g. knowing what they are seeing is not real, and how the false experiences affect behavior. Negative symptoms are not commonly described as part of PD psychosis, although apathy, emotional flattening, and other overlapping elements of schizophrenic negative behaviors are often associated with PD in general. Finally, decline in ability to function in schizophrenia is thought to be directly attributable to progression of the psychiatric syndrome, while PD psychosis is more often considered to be associated with administration of exogenous dopaminergic drugs and parallel to progression in other PD-related symptoms such as cognitive impairment.
Dr. Juncos
I agree with my colleagues that the most common psychotic symptom in PD is visual hallucinations. In PD without dementia, there is a gradual progression from visual illusions with retained insight, to visual hallucinations in the setting of an otherwise clear sensorium and no major mood disturbance. In contrast, in primary psychiatric conditions and in dementia, the last two conditions are almost always present. Historically hallucinations in PD first appear during transitions from wakefulness to sleep and vice-versa during twilight hours. The more cognitively impaired the patient is, the more likely the experience will be upsetting and trigger a reaction. They may retain insight early on and be easily convinced that the experienced is not real. In a very stereotyped manner, patients report that the images and characters in the hallucination do not talk or respond to the patient. The patient may “hear” background mumbling coming from the direction of the hallucination and see the lips of the figures moving. If the patient tries to reach out and touch the figures, they typically disappear. ‘Lilliputian hallucinations’, that is seeing diminutive people, is another peculiar and not uncommon form of drug-induced hallucination in PD.
Delusions are typically less common but more disturbing than the hallucinations and suggest that the person is more cognitively impaired. They are more difficult to treat and more difficult for families to cope with. Like in Alzheimer’s disease, these delusions typically surround themes of infidelity and of valuables being hidden or stolen from the patient. Of special note is the ‘Capgras’ syndrome, a misidentification syndrome in which the patient believes that a close person has been replaced by an impostor.
Considering most recent research, what do we now know about the cause of these symptoms?
Dr. Friedman
We still do not know much about the cause. It is of great interest that the hallucinations and delusions are identical to those seen in patients with dementia with Lewy bodies who are not taking any PD medications. The major risk factors for these symptoms are dementia and REM sleep behavior disorder, although impaired vision also adds some increased risk. However a report from last year noted that a significant percentage of non-demented PD patients had very occasional passage hallucinations or presence hallucinations prior to being diagnosed with PD.
Dr. Pontone
Not enough. While there is an emerging consensus about which brain regions are likely involved, more research is needed to better understand the mechanistic basis of psychosis in PD. Currently even the neurochemical substrates of PD psychosis are disputed, however it is generally agreed that dopamine, acetylcholine, and serotonin are likely involved to some extent. A number of studies demonstrate that the prevalence of psychosis is higher in patients treated with dopamine replacement therapies compared to those who are drug naïve, however the relationship is not necessarily linear, e.g. incidence does not increase with increasing levodopa dose. Reduced acetylcholine levels are associated with cognitive impairment and dementia in PD and are suspected of contributing to the risk of PD psychosis. However, strategies to restore acetylcholine such as acetylcholinesterase inhibitors do not reliably improve psychosis and many patients without dementia or significant cognitive impairment experience PD psychosis. Serotonin, serotonergic neurons, or possibly 5HT-2A receptor dysregulation, might also play a role directly or indirectly in the production of psychotic symptoms. Many atypical antipsychotics and the new antipsychotic for PD, pimavanserin, work by modulating serotonin (e.g. inverse agonist) at 5HT-2A receptors.
Dr. Juncos
Advanced age and advanced symptoms are the major risk factors clearly indicating that the more advanced the PD pathology, the higher the risk for psychotic symptoms. Anatomic pathways that have been linked to the pathophysiology of hallucinations in PD include dysfunctions in visual pathways from the retina to the visual cortex, to visual association areas. There are also functional alterations in other regions connected to the frontal cortex, such as the corticostriatal changes resulting from dopamine denervation. Biochemically, increased dopaminergic transmission mediated by dopaminergic drug treatment in PD, which is related to receptor hypersensitivity, clearly plays an important role in hallucinations. Dopamine receptor blockers can thus alleviate the severity of psychotic symptoms but generally not eliminate them altogether suggesting other mechanism are also at play. Better discrimination of the phenomenology combined with more research on pathophysiology is needed to increase our understanding of mechanisms, prevention, better therapeutic options and prognosis.
Other co-occurring conditions in PD like dementia, depression, chronic insomnia and parasomnias, and chronic exposure to various psychotropics, increase the vulnerability of PD patients to psychotic symptoms. In these cases, the presentation may be more complex than what was described above and may be more difficult to treat.
It is also common for PD patients with psychotic symptoms to have sleep disturbances ranging from insomnia to frequent awakening due to various causes such as urinary symptoms, the nocturnal re-emergence of PD symptoms and concurrent affective illness. In my experience, to effectively manage psychotic symptoms, it is imperative to also address the insomnia and its potential causes early in the treatment of psychosis.
Since it is clear that not all patients treated PD develop hallucinations, there is a clear individual vulnerability that remains to be elucidated. Given the many studies using dopamine and serotonin antagonists/inverse agonists (e.g. quetiapine, olanzapine, pimavanserin) that have either failed or demonstrated a modest effect at eliminating hallucinations, it is clear that the mechanism probably extends beyond modulating dopamine or serotonin receptors hypersensitivity and hyperstimulation. The higher frequency of these phenomena in PD with dementia indicates that cholinergic pathology probably plays a role as seen in LBD and PD-Alzheimer disease, and thus, the role of acetylcholinesterase inhibitors as mentioned above. Moving forward it will be important to establish early on, in which patient can these symptoms be simply tolerated and monitored, and in which are the symptoms likely to progress if not controlled aggressively. Finally, given the key role of sleep-wake transitions in the initial presentation of these symptoms, and the importance of improving sleep to control hallucinations, what role does abnormal sleep play in the generation of these symptoms?
What would you recommend for general management of psychotic symptoms in PD?
Dr. Friedman
When psychotic symptoms develop, they need to be discussed with the patient, but not always treated. All experts agree that contributing causes such as medical illnesses, particularly infections, need to be considered, and that non-PD related medications, particularly anticholinergics used for overactive bladder problems, should be reduced or eliminated, if possible. When these have been reduced as much as possible, then PD medications should be reduced to the lowest level tolerated. If after all these measures, psychotic symptoms are a problem then they should be treated. There have been no comparative trials of medications for PD psychosis. Cholinesterase inhibitors have been recommended for those PD psychosis patients who are demented. Clozapine has been shown to be extremely effective and is approved for this purpose in some countries, but not the U.S. Pimavanserin, a novel, non-dopamine receptor blocking drug, has been shown to be effective and is currently approved only in the U.S. Questions have recently been raised about safety, but there are few reliable data. While three double blind, placebo controlled trials of quetiapine have failed, many experts continue to recommend its use.
In choosing between clozapine and cholinesterase inhibitors or pimavanserin, the time to improvement must be considered. Publications show that within 7 days on clozapine patients are considerably improved whereas the pimavanserin data indicate that benefit begins by 4 weeks and peaks at 6. There are no data on time to improvement with cholinesterase inhibitors, but they probably take about 6-8 weeks. I recommend quetiapine or clozapine for patients who are in distress and need rapid improvement. For patients with tolerable although bothersome psychotic problems I recommend pimavanserin, although cholinesterase inhibitors should be considered. Although the doses of clozapine required are very low, the risk of leukopenia and agranulocytosis remains the same, unrelated to dose, and thus, blood monitoring is required. It should be noted that although clozapine and quetiapine are often given twice or three times daily for schizophrenia, a single bedtime dose is usually adequate in PD.
Dr. Pontone
Antipsychotic medication is often used to treat hallucinations, delusions, and behavioral disturbances resulting from PD psychosis. However, typical and most atypical antipsychotics with even moderate affinity for the D2 dopamine receptor should be avoided in PD psychosis due to adverse motor effects. A Movement Disorder Society review deemed only clozapine, quetiapine, and pimavanserin as safe for use in PD psychosis, because these drugs have low or no appreciable affinity for the D2 receptor (Seppi et al., 2011). However, quetiapine lacks evidence for efficacy, and all three agents may potentially increase the risk of mortality in elderly PD patients with dementia-related psychosis.
In non-demented PD with psychosis pimavanserin is likely to be the best tolerated and easiest to prescribe as dose titration is generally unnecessary. For PD psychosis that occurs with significant sleep-wake disruption or agitation I often consider quetiapine first-line. Quetiapine is sedating and can help patients fall asleep, reduce agitation, and can be used in a PRN fashion for break through behavioral disturbances without too much risk of prolonged somnolence due to a relatively short (six hour) half-life. Due to the greater risk of adverse effects and need for frequent blood monitoring, I typically reserve clozapine for cases that have failed to respond to both quetiapine and pimavanserin.
What are common presentations of psychotic symptoms in PD and how do they differ from other disorders?
Dr. Friedman
Hallucinations are far and away the most common of the psychotic symptoms. These are primarily visual, with auditory about half as common and others, primarily tactile, much less. In addition, PD patients often report “presence hallucinations,” which are a feeling of someone or something else present, generally behind or to the side, just out of view. When the patient looks for the person or animal, there is nothing there. These are not truly hallucinations, but we use that terminology anyway. “Passage hallucination” is the term used for visual hallucinations, which occur in the peripheral visual field. They are usually shadows or cats or dogs passing by, but when the person looks at them, the images disappear. The “major” hallucinations, are typically visual, of non-threatening people or animals, ignoring the patient. They tend to recur, and usually are the same image each time. Auditory hallucinations tend to be a bit different, music coming from a different room, the radio playing, people talking in the corridor but cannot be understood. Tactile hallucinations are usually the sense of a small animal or insect crawling on the skin. They are usually annoying but not so bothersome as they sound. Olfactory and gustatory hallucinations are rare.
Delusions, false, irrational beliefs not based on real data, are generally paranoid, with feeling of spousal infidelity, thoughts that caretakers are stealing or misplacing objects on purpose, or that the patient is to be institutionalized. In primary psychiatric disorders, like schizophrenia or severe depression with psychosis, the hallucinations are generally auditory and have significant emotional importance, saying bad and denigrating things when the patient feels poorly about himself, or wonderful things if he has delusions of grandeur.
Dr. Pontone
Historically, schizophrenia is held to be the quintessential example of a psychotic disorder. Symptoms most often include auditory hallucinations, hearing several voices talking about or to the afflicted and delusional thoughts, which are false, fixed, idiosyncratic beliefs. Disorganized speech and behavior are also symptoms of schizophrenia. In addition to these “positive symptoms”, schizophrenics can have “negative symptoms” such as neglect of personal duties like hygiene, socialization, and may even lack the motivation to participate in everyday activities. Together these symptoms cause a distressing psychiatric syndrome, which results in a “downward spiral” with decreasing ability to function in daily life and increasing difficulty differentiating hallucinatory experiences from reality.
Psychosis in PD differs from schizophrenia at both the level of the symptom and syndrome. For example, auditory hallucinations are much more common than visual hallucinations in schizophrenia, while the reverse is true in PD. Similarly, delusions occur in almost all persons affected by schizophrenia, but are present only in a minority of persons with PD. In addition to quantitative differences in which sensory modality is affected and how frequently delusions occur, there may also be qualitative differences in how the symptoms are experienced such as greater preservation of insight in PD psychosis, e.g. knowing what they are seeing is not real, and how the false experiences affect behavior. Negative symptoms are not commonly described as part of PD psychosis, although apathy, emotional flattening, and other overlapping elements of schizophrenic negative behaviors are often associated with PD in general. Finally, decline in ability to function in schizophrenia is thought to be directly attributable to progression of the psychiatric syndrome, while PD psychosis is more often considered to be associated with administration of exogenous dopaminergic drugs and parallel to progression in other PD-related symptoms such as cognitive impairment.
Dr. Juncos
I agree with my colleagues that the most common psychotic symptom in PD is visual hallucinations. In PD without dementia, there is a gradual progression from visual illusions with retained insight, to visual hallucinations in the setting of an otherwise clear sensorium and no major mood disturbance. In contrast, in primary psychiatric conditions and in dementia, the last two conditions are almost always present. Historically hallucinations in PD first appear during transitions from wakefulness to sleep and vice-versa during twilight hours. The more cognitively impaired the patient is, the more likely the experience will be upsetting and trigger a reaction. They may retain insight early on and be easily convinced that the experienced is not real. In a very stereotyped manner, patients report that the images and characters in the hallucination do not talk or respond to the patient. The patient may “hear” background mumbling coming from the direction of the hallucination and see the lips of the figures moving. If the patient tries to reach out and touch the figures, they typically disappear. ‘Lilliputian hallucinations’, that is seeing diminutive people, is another peculiar and not uncommon form of drug-induced hallucination in PD.
Delusions are typically less common but more disturbing than the hallucinations and suggest that the person is more cognitively impaired. They are more difficult to treat and more difficult for families to cope with. Like in Alzheimer’s disease, these delusions typically surround themes of infidelity and of valuables being hidden or stolen from the patient. Of special note is the ‘Capgras’ syndrome, a misidentification syndrome in which the patient believes that a close person has been replaced by an impostor.
Considering most recent research, what do we now know about the cause of these symptoms?
Dr. Friedman
We still do not know much about the cause. It is of great interest that the hallucinations and delusions are identical to those seen in patients with dementia with Lewy bodies who are not taking any PD medications. The major risk factors for these symptoms are dementia and REM sleep behavior disorder, although impaired vision also adds some increased risk. However a report from last year noted that a significant percentage of non-demented PD patients had very occasional passage hallucinations or presence hallucinations prior to being diagnosed with PD.
Dr. Pontone
Not enough. While there is an emerging consensus about which brain regions are likely involved, more research is needed to better understand the mechanistic basis of psychosis in PD. Currently even the neurochemical substrates of PD psychosis are disputed, however it is generally agreed that dopamine, acetylcholine, and serotonin are likely involved to some extent. A number of studies demonstrate that the prevalence of psychosis is higher in patients treated with dopamine replacement therapies compared to those who are drug naïve, however the relationship is not necessarily linear, e.g. incidence does not increase with increasing levodopa dose. Reduced acetylcholine levels are associated with cognitive impairment and dementia in PD and are suspected of contributing to the risk of PD psychosis. However, strategies to restore acetylcholine such as acetylcholinesterase inhibitors do not reliably improve psychosis and many patients without dementia or significant cognitive impairment experience PD psychosis. Serotonin, serotonergic neurons, or possibly 5HT-2A receptor dysregulation, might also play a role directly or indirectly in the production of psychotic symptoms. Many atypical antipsychotics and the new antipsychotic for PD, pimavanserin, work by modulating serotonin (e.g. inverse agonist) at 5HT-2A receptors.
Dr. Juncos
Advanced age and advanced symptoms are the major risk factors clearly indicating that the more advanced the PD pathology, the higher the risk for psychotic symptoms. Anatomic pathways that have been linked to the pathophysiology of hallucinations in PD include dysfunctions in visual pathways from the retina to the visual cortex, to visual association areas. There are also functional alterations in other regions connected to the frontal cortex, such as the corticostriatal changes resulting from dopamine denervation. Biochemically, increased dopaminergic transmission mediated by dopaminergic drug treatment in PD, which is related to receptor hypersensitivity, clearly plays an important role in hallucinations. Dopamine receptor blockers can thus alleviate the severity of psychotic symptoms but generally not eliminate them altogether suggesting other mechanism are also at play. Better discrimination of the phenomenology combined with more research on pathophysiology is needed to increase our understanding of mechanisms, prevention, better therapeutic options and prognosis.
Other co-occurring conditions in PD like dementia, depression, chronic insomnia and parasomnias, and chronic exposure to various psychotropics, increase the vulnerability of PD patients to psychotic symptoms. In these cases, the presentation may be more complex than what was described above and may be more difficult to treat.
It is also common for PD patients with psychotic symptoms to have sleep disturbances ranging from insomnia to frequent awakening due to various causes such as urinary symptoms, the nocturnal re-emergence of PD symptoms and concurrent affective illness. In my experience, to effectively manage psychotic symptoms, it is imperative to also address the insomnia and its potential causes early in the treatment of psychosis.
Since it is clear that not all patients treated PD develop hallucinations, there is a clear individual vulnerability that remains to be elucidated. Given the many studies using dopamine and serotonin antagonists/inverse agonists (e.g. quetiapine, olanzapine, pimavanserin) that have either failed or demonstrated a modest effect at eliminating hallucinations, it is clear that the mechanism probably extends beyond modulating dopamine or serotonin receptors hypersensitivity and hyperstimulation. The higher frequency of these phenomena in PD with dementia indicates that cholinergic pathology probably plays a role as seen in LBD and PD-Alzheimer disease, and thus, the role of acetylcholinesterase inhibitors as mentioned above. Moving forward it will be important to establish early on, in which patient can these symptoms be simply tolerated and monitored, and in which are the symptoms likely to progress if not controlled aggressively. Finally, given the key role of sleep-wake transitions in the initial presentation of these symptoms, and the importance of improving sleep to control hallucinations, what role does abnormal sleep play in the generation of these symptoms?
What would you recommend for general management of psychotic symptoms in PD?
Dr. Friedman
When psychotic symptoms develop, they need to be discussed with the patient, but not always treated. All experts agree that contributing causes such as medical illnesses, particularly infections, need to be considered, and that non-PD related medications, particularly anticholinergics used for overactive bladder problems, should be reduced or eliminated, if possible. When these have been reduced as much as possible, then PD medications should be reduced to the lowest level tolerated. If after all these measures, psychotic symptoms are a problem then they should be treated. There have been no comparative trials of medications for PD psychosis. Cholinesterase inhibitors have been recommended for those PD psychosis patients who are demented. Clozapine has been shown to be extremely effective and is approved for this purpose in some countries, but not the U.S. Pimavanserin, a novel, non-dopamine receptor blocking drug, has been shown to be effective and is currently approved only in the U.S. Questions have recently been raised about safety, but there are few reliable data. While three double blind, placebo controlled trials of quetiapine have failed, many experts continue to recommend its use.
In choosing between clozapine and cholinesterase inhibitors or pimavanserin, the time to improvement must be considered. Publications show that within 7 days on clozapine patients are considerably improved whereas the pimavanserin data indicate that benefit begins by 4 weeks and peaks at 6. There are no data on time to improvement with cholinesterase inhibitors, but they probably take about 6-8 weeks. I recommend quetiapine or clozapine for patients who are in distress and need rapid improvement. For patients with tolerable although bothersome psychotic problems I recommend pimavanserin, although cholinesterase inhibitors should be considered. Although the doses of clozapine required are very low, the risk of leukopenia and agranulocytosis remains the same, unrelated to dose, and thus, blood monitoring is required. It should be noted that although clozapine and quetiapine are often given twice or three times daily for schizophrenia, a single bedtime dose is usually adequate in PD.
Dr. Pontone
Antipsychotic medication is often used to treat hallucinations, delusions, and behavioral disturbances resulting from PD psychosis. However, typical and most atypical antipsychotics with even moderate affinity for the D2 dopamine receptor should be avoided in PD psychosis due to adverse motor effects. A Movement Disorder Society review deemed only clozapine, quetiapine, and pimavanserin as safe for use in PD psychosis, because these drugs have low or no appreciable affinity for the D2 receptor (Seppi et al., 2011). However, quetiapine lacks evidence for efficacy, and all three agents may potentially increase the risk of mortality in elderly PD patients with dementia-related psychosis.
In non-demented PD with psychosis pimavanserin is likely to be the best tolerated and easiest to prescribe as dose titration is generally unnecessary. For PD psychosis that occurs with significant sleep-wake disruption or agitation I often consider quetiapine first-line. Quetiapine is sedating and can help patients fall asleep, reduce agitation, and can be used in a PRN fashion for break through behavioral disturbances without too much risk of prolonged somnolence due to a relatively short (six hour) half-life. Due to the greater risk of adverse effects and need for frequent blood monitoring, I typically reserve clozapine for cases that have failed to respond to both quetiapine and pimavanserin.
Dr. Juncos
I agree with my colleagues above and have a few comments to add. Having ruled out intervening medical condition, and having determined that the patient has reached the lowermost dose of antiparkinsonian therapy they can tolerate and still move, I agree with Dr. Friedman that the most important next step is deciding, does the patient still need antipsychotic treatment? This need appears more pressing in patients with PD and dementia, whereas mindful monitoring may be possible in select patients who are not demented. The control timetable needed in a given individual is key, but also improved sleep should be an early target. Finally, the behavior of our colleagues who continue to use quetiapine for PD hallucinations in spite of negative results in randomized trials goes beyond tenaciousness. From experience, community neurologists continue to use quetiapine based on their broader definition of ‘success’ in treating hallucinations because they are including improved sleep, anxiety and agitation, even if the hallucinations are still present. Is there something to be learned from this experience for future studies?
I agree with my colleagues above and have a few comments to add. Having ruled out intervening medical condition, and having determined that the patient has reached the lowermost dose of antiparkinsonian therapy they can tolerate and still move, I agree with Dr. Friedman that the most important next step is deciding, does the patient still need antipsychotic treatment? This need appears more pressing in patients with PD and dementia, whereas mindful monitoring may be possible in select patients who are not demented. The control timetable needed in a given individual is key, but also improved sleep should be an early target. Finally, the behavior of our colleagues who continue to use quetiapine for PD hallucinations in spite of negative results in randomized trials goes beyond tenaciousness. From experience, community neurologists continue to use quetiapine based on their broader definition of ‘success’ in treating hallucinations because they are including improved sleep, anxiety and agitation, even if the hallucinations are still present. Is there something to be learned from this experience for future studies?