Dr. Marsh is associate professor in the Departments of Psychiatry and Neurology at the Johns Hopkins University School of Medicine in Baltimore, MD, and director of the Clinical Research Program of the Johns Hopkins Morris K. Udall Parkinson’s Disease Research Center of Excellence.

Disclosure: Dr. Marsh is a consultant to Ovation; has received grant/research support from Eli Lilly, Forest, the National Institute of Health (grants nos. MH 06766, P50-N538377, R01-HD39822), and the National Parkinson’s Foundation; and has received honoraria from AstraZeneca, Ortho-McNeil, and Pfizer.

Please direct all correspondence to: Laura Marsh, MD, Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, 600 N. Wolfe St, Phipps 300-C, Baltimore, MD 21287; Tel: 410-502-6945; Fax: 410-614-3676; E-mail: lmarsh@jhmi.edu.


 

Focus Points

• Psychosis is a common psychiatric comorbidity of Parkinson’s disease (PD).

• Visual hallucinations are the most common psychotic symptom in PD, but other forms of hallucinations and delusions occur and frequently accompany visual hallucinations.

• The development of PD-related psychosis is invariably related to dopaminergic therapies, but non-dopaminergic factors, such as dementia, other medications, and medical illness, are also relevant.

• Treatment of psychosis can be challenging because of the need to balance the relative benefits and adverse effects of antiparkinsonian and antipsychotic therapies and address additional neuropsychiatric and medical comorbidities.

 

Abstract

Psychotic symptoms are common in Parkinson’s disease (PD), affecting nearly 50% of all patients over the course of the disease. The form and severity of psychotic symptoms varies, ranging from nondistressing hallucinations in any sensory modality to complex visual hallucinations and delusions. PD patients with psychosis often come to psychiatric attention when serious behavioral disturbances develop. Anti-parkinsonian therapies are a primary factor in the development of psychosis, but PD-related psychoses are not exclusively drug-induced. Nondopaminergic factors are also relevant, including cognitive impairment, mood disorders, visual acuity, sleep disturbances, other medication effects, and delirium. Management involves addressing multiple issues, including modifiable risk factors. Because psychosis impacts patient function and caregiver burden, the clinical care of PD patients should entail routine monitoring for psychosis, re-assessment of the therapeutic regimen, and attention to any remediable risk factors. Antipsychotic medications are indicated when symptoms are distressing or disruptive, but their use requires consideration of potential adverse motor and cognitive side effects.  

 

Introduction

Psychosis is a common neuropsychiatric complication of Parkinson’s disease (PD) and a major therapeutic challenge. In general, psychosis emerges as an adverse effect of antiparkinsonian therapy in later stages of the disease.  At that juncture, motor symptoms are advanced and more difficult to control; dementia, medical and other psychiatric comorbidities, and caregiver strain are also frequent.1,2 While effective management of psychosis reduces morbidity, treatment is complex because antipsychotic medications can aggravate motor and cognitive impairments, antiparkinsonian treatments can contribute to psychopathology, and patients are frail. Even though atypical antipsychotics have improved prognosis,3 psychosis remains the most important risk factor for nursing home placement in PD4 and is associated with increased mortality.3

This review describes the phenomenology, risk factors, and treatments of PD-related psychosis. Psychiatrists tend to become involved only with more complex cases since most PD treatment is under the purview of neurologists and is outpatient based. Thus, direct psychiatric care is often requested for more emergent problems that present in emergency rooms, inpatient medical units, or long-term care facilities or when inpatient psychiatric treatment is needed. Safe and effective treatment of psychosis entails a comprehensive approach with awareness of its various presentations, attention to modifiable risk factors, and knowledge of the effects of different treatment strategies on motor function and drug interactions.

 

Epidemiology

Psychotic symptoms in PD include hallucinations and delusions. There may or may not be associated associated behavioral changes.2,5 Prevalence rates, ranging from 8% to 40%, vary according to the study sample and study definitions of psychosis, cognitive impairment, and PD. Visual hallucinations are most common, seen cross-sectionally in 15% to 40% of patients. In a cohort from a movement disorders clinic, lifetime prevalence of all types of visual hallucinations was almost 50%.5 Prevalence rates in a community-based sample were 9.8% for hallucinations with retained insight and 6% for more severe hallucinations or delusions.1 Delusions are less common and usually occur with hallucinations; prevalence varies from 3% to 30%.2,6  

Psychosis is more common in patients with dementia (40% versus 15% in non-demented patients), with rates increased to 70% in patients with dementia if minor visual hallucinations (Table 1) are included.1  Less than half of patients had visual hallucinations in other modalities.2,5 Auditory hallucinations are reported in 8% to 13%,2,5,7 and may be underappreciated. Olfactory, tactile, and somatic hallucinations are less common and generally occur with visual hallucinations.2,8 

 

Clinical Characteristics

PD-related psychosis ranges in severity and generally falls into three main categories.9 Benign psychosis refers to hallucinations with retained insight into the “non-real” nature of the experience. In such cases, there is no distress and some find their experiences amusing. A second category includes hallucinations or delusions in a clear sensorium (ie, the absence of delirium), but with diminished insight. Some patients are indifferent to their psychotic experiences while others become preoccupied or distressed. Delusions can lead to serious behavioral problems, including aggression. A third group includes hallucinations and delusions in the context of delirium, which can be superimposed on chronic PD-related psychosis.

Hallucinations  

Hallucinations can occur in any sensory modality (Table 1).2,5,7,8,10-13 Minor hallucinations and illusions are most common (26%).5 These rarely cause behavioral disturbances, but reactions to abnormal perceptions or illusions may affect safety while driving or walking at night, even with retained insight. The content of hallucinations can vary, but many describe recurrent phenomena. Visual hallucinations frequently manifest in dim light, but they can occur any time of day, inside or outside. Patients with compromised insight may attempt to feed their “visitors” or respond aggressively to visual hallucinations they perceive as threatening.

 

Delusions

Delusions in PD are usually of a paranoid nature. Paranoid ideation can be nonspecific, especially when dementia is severe. More frequently, patients have well-systematized ideas that focus on a single theme. Patients describe delusions of jealousy or spousal infidelity, fears of being poisoned, elaborate schemes about people (sometimes including their physicians) who conspire against them, somatic delusions, and delusions of control that others commit actions that aggravate their motor symptoms. Delusional misidentification (eg, Capgras phenomena) has been reported.14 Mood congruent delusions may accompany depressive disorders, but delusional ideation is usually independent of a comorbid mood disorder.2,15 Similarly, delusions often occur in the context of visual hallucinations, and the delusional content may be either unrelated or directly related to other psychopathology, such as hypersexual or manic phenomena.  Patients with mood fluctuations associated with on/off motor fluctuations may have persecutory delusions when “off” and grandiose delusions when “on.”

 

Longitudinal Course  

Longitudinal studies in new onset idiopathic PD are needed to clarify when psychosis is most likely to develop. Early onset of psychosis after initiation of dopaminergic therapy, ie, within the first 3 months, is atypical for PD and suggests alternative diagnoses. In most patients, psychosis is chronic.16 Severe psychosis requiring antipsychotic therapy is associated with persistent symptoms, development and progression of dementia, a higher likelihood of nursing home placement, and death.3  

 

Neuropsychiatric Comorbidities

Affective Disorders

Nonpsychotic psychiatric disturbances often co-occur with psychosis. Depressive symptoms (or disorders) are especially common,1,5,10,12,15,17 although psychotic affective syndromes are infrequent.1,15 In a longitudinal study2 of 116 PD patients, 56% of those with psychosis (hallucinations and/or delusions) had an additional syndromic psychiatric disturbance, including depression (71%), anxiety (21%), apathy (14%), and/or delirium (14%). This additional psychopathology was associated with greater cognitive impairment and caregiver distress.  While psychosis predicted caregiver burden, depressive symptoms added to functional impairment. Thus, detection and treatment of mood disorders in PD-related psychosis should reduce morbidity and caregiver distress.  

 

Disruptive Behaviors  

Disinhibited behaviors, while uncommon, may accompany psychosis and often lead to psychiatric referral when they are disruptive. They are usually related to dopaminergic therapy, but underlying disease progression plays a role18 or the behaviors may develop after neurosurgical treatments for PD.19 Some patients abuse dopaminergic medications,20 thus, leading to drug-induced motor complications, psychosis, and other behavioral disturbances. Hypersexual behaviors range from enhanced libido with increased sexual activity to new-onset paraphilias.21 Fluctuating levodopa effects can be associated with an enhanced sense of well being, euphoria, hypomania, or mania during “on” states along with mood-congruent psychotic symptoms and inappropriate or risky goal-directed behaviors.22 Perseverative behaviors and pathological gambling and shopping are also described.18 Often, these disturbances are difficult to manage, especially when their covert or embarrassing nature or delusions keep patients from being forthcoming.  

 

Cognitive Impairment and Dementia  

Cognitive impairment is one of the most consistently reported correlates of psychosis.1,5,12,15,17 The cross-sectional prevalence of dementia in PD ranges from 15% to 30%, while the cumulative prevalence of dementia in PD over 8 years was 75% in one longitudinal population-based sample.23 Since selective cognitive deficits involving executive functions and memory retrieval are evident early in the course of the disease in most patients,24 it is of interest whether certain cognitive deficits predict onset of psychosis.  Cross-sectionally, hallucinators show greater deficits on letter fluency as well as global cognitive performance.17  Another study showed impaired object perception, recognition memory, and nonverbal recall in visual hallucinators compared to nonhallucinators and non-PD age-matched controls.25 In a separate series, global and frontal lobe functions were more impaired in hallucinating and/or delusional patients compared to patients without any comorbid psychiatric disturbances.2 Although greater executive dysfunction is associated with transition to dementia,26 it is unclear whether such selective impairments represent an earlier risk factor or marker for development of psychosis that might be a therapeutic target.  

 

Etiology and Risk Factors

The pathophysiology of psychosis in PD is unknown (Table 2). Rare reports of PD-related psychosis before the advent of levodopa therapy supports a primary role for dopaminergic therapy.27 All agents, including dopamine agonists, amantadine, and levodopa, can cause psychosis that improves with dose reduction; some agents, namely dopamine agonists, carry a higher risk. A popular explanation attributes psychosis to secondary dopamine receptor hypersensitivity in mesocortical and mesolimbic regions because of overstimulation by dopaminergic medications.17 Since dopaminergic therapy reduces serotonin levels, other theories invoke an imbalance between dopaminergic and serotonergic systems28 or overstimulation of serotonergic receptors by dopaminergic medications.29


A role for nondopaminergic neurotransmitter systems as well as other patient-related factors is suggested by the lack of a direct dose-effect relationship between psychosis and dopaminomimetic medications1 or levodopa plasma level.30 Cognitive impairment, particularly dementia, older age, longer disease duration, more severe PD, sleep/wake disturbances, and depression are most consistently cited.1,5,12,15,31,32 Concurrent medical conditions can lead to psychosis, including in the context of delirium, as can medications, including selegiline, amantadine, anticholinergic agents, and psychoactive medications that may be prescribed unwittingly to vulnerable patients, eg, benzodiazepines, opiates, and certain antidepressants. A patient with an underlying brain disease such as PD may be more vulnerable to developing psychosis when there are comorbid affective disorders.2 Rapid eye movement sleep behavior disorder33 and sleep disturbances in general34 are also associated with visual hallucinations in PD, suggesting a link with sleep pathophysiology. Visual dysfunction is another risk factor.5,12 Genetic factors have not been established.  

Since cognitive impairment in PD is associated with a cholinergic deficiency35 and the most consistent clinical correlate of psychosis is cognitive impairment, cholinergic deficits are also thought to play a role in the development of psychosis. Anticholinergic medications are associated with delirium as well as psychotic symptoms in a clear sensorium. Cortical Lewy body pathology may be related to development of psychosis in later stages of PD, including delirium-like states of fluctuating consciousness that are present in dementia with Lewy bodies (DLB).

 

Overlap of Psychosis in Parkinson’s Disease and Dementia with Lewy Bodies

There is controversy as to whether PD and DLB represent separate disorders or occur on a spectrum of a single disease entity related to Lewy body pathology.36,37 Clinically, both DLB and advanced stage PD can present cross-sectionally with parkinsonism, dementia, and psychosis.  Pathologically, Lewy bodies characterize both conditions, and some PD patients with dementia have sufficient numbers of cortical Lewy bodies to meet neuropathological criteria for DLB. However, on clinical grounds, distinguishing DLB from PD-related psychosis may be important because of potential differences in prognosis and treatment planning.  

The temporal evolution of neuropsychiatric and motor symptoms and response to antiparkinsonian and antipsychotics help distinguish PD and DLB, despite shared clinical and biological features. Clinically, DLB is a progressive dementia that affects memory, attention, frontal-subcortical functions, and visuospatial abilities, which are evident with the onset of illness. Current clinical criteria for probable DLB require dementia onset within 1 year after onset of parkinsonism.38 Two of either hallucinations, parkinsonism, or fluctuating levels of arousal are required for the diagnosis of probable DLB. Alternative diagnoses to idiopathic PD, including DLB, Alzheimer’s disease, or pre-existing psychopathology, are suggested when dementia or psychosis presents before onset of parkinsonism or early in the course after onset of motor signs.39 DLB should be strongly considered when hallucinations, particularly visual hallucinations, occur before initiation of antiparkinsonian treatment.  In autopsy-proven cases, diagnosis of DLB was more likely than PD when motor signs included myoclonus, absence of rest tremor, nonresponse to levodopa, or no perceived need to treat with levodopa.40 Controlled levodopa trials are needed in DLB, but it is commonly observed that cognitive and psychiatric effects occur at much lower levodopa doses in DLB than PD and psychosis. In addition, neuroleptic sensitivity, even to atypical agents, is greater in DLB and associated with increased mortality.41 Whereas clozapine is safe and effective in PD, it is poorly tolerated in DLB, suggesting greater sensitivity to its anticholinergic effects. However, cholinesterase inhibitors reduce psychosis and improve cognition in both conditions.41  

 

Clinical Management

Table 342 provides “steps” in the treatment of psychosis. Symptom severity and consideration of remediable causes or triggers should guide which interventions are taken. “Benign” symptoms may only need education and reassurance. Psychosis with agitation may require emergent hospitalization to treat concurrent medical conditions, maintain safety of the patient and others, and control behavior, yet enable adequate motor function while adjusting medications or adding antipsychotics. Pharmacotherapy is complicated as antiparkinsonian medications contribute to psychosis and antipsychotic agents can aggravate motor and cognitive impairments.

 

Nonpharmacologic Treatments  

Education is a critical component of management. Before starting antiparkinsonian therapy, patients and family members should be warned about the potential for psychotic symptoms and encouraged to report them. When psychosis occurs, patients and caregivers often need reassurance that they are not “going crazy.” Family members need instructions on management, including how to react when patients lack insight and respond to hallucinations or delusions, assess for environmental triggers of confusion, psychosis, or agitation, and when to seek additional help. Assistance with referrals for respite care, adult day programs, or institutionalized placement is also incorporated into treatment.  

 

Medication Adjustments

After evaluating their utility and redundancy, antiparkinsonian and other medications should be either eliminated or reduced to the lowest effective dose. “Drug holidays” are no longer recommended because they cause patients extreme discomfort and pose medical risks, including neuroleptic malignant syndrome (NMS).43 Among the antiparkinsonian agents, levodopa provides optimal motor symptom control and seems to be less likely to lead to psychotic symptoms. Thus, before reducing levodopa, it is customary to eliminate other agents in the following order: anticholinergics, selegiline, amantadine, dopamine agonists, and catechol-O-methyltransferase inhibitors. As medications are reduced, motor symptoms may increase, and relative effects on psychiatric status, mobility, and caregiver burden need to be considered. Motor response is more predictable with standard levodopa formulations than with controlled-release preparations.  

 

Treatment of Other Neuropsychiatric Conditions

Affective Disorders

Patients with psychosis should be screened for mood disorders, namely depressive disorders, which are underrecognized.44 Anxiety disturbances are also overlooked.45 These disturbances are generally treated with antidepressants, though nonpharmacologic therapies may be effective for milder cases.  Importantly, mood disorders should be treated aggressively with the goal of remission. There have been a limited number of antidepressant treatment trials for PD-related depression and all have had methodological limitations.46 Accordingly, there are no specific recommendations to date regarding which antidepressants are better tolerated or if certain antidepressant classes are more effective than others

 

Electroconvulsive Therapy  

Severe depression, especially with mood congruent delusions, is the main indication for electroconvulsive therapy (ECT). ECT, including maintenance regimens, has been used to treat psychosis in PD,47,48 but parkinsonism and on-off fluctuations also improve.49 Thus, ECT is an option when psychosis is resistant to medications or antipsychotics are not tolerated.  

 

Sleep Disturbances

Resolution of psychosis often improves sleep patterns. However, psychosis with disrupted sleep creates a cycle of nocturnal agitation and daytime somnolence that may improve with direct treatment of insomnia. Antiparkinsonian agents may need adjusting to avoid nocturnal “wearing off” and improve sleep consolidation. Trazodone, beginning at 25–50 mg and repeating if needed up to 200 mg, is often effective. Other sedating antidepressants at low doses can also be effective hypnotics, eg, nortriptyline 10–25 mg, mirtazapine 7.5–15 mg. Low dose quetiapine (starting dose is usually 6.25–12.5 mg) is a common hypnotic and antipsychotic in this population. For daytime agitation, trazodone 25 mg Q6 hours PRN can be an effective strategy that avoids the relatively greater sedation resulting from benzodiazepines or antipsychotics. Benzodiazepine hypnotics, antihistamines, and new-generation nonbenzodiazepine hypnotics (eg, zolpidem) tend to increase confusion, while they may be initially effective. Nocturia and sleep apnea should be addressed. Daily exercise and activity facilitate nocturnal sleep. Modafinil or amphetamines may promote daytime wakefulness, although they carry an added risk of psychosis.

 

Cognitive Impairment

Based on the established cholinergic deficit in PD and reports that cholinesterase inhibitors improved cognitive and neuropsychiatric symptoms in Alzheimer’s disease and DLB without aggravating parkinsonism,50 initial studies of cholinesterase inhibitors in PD aimed at improving hallucinations.  Open-label studies of tacrine,51 rivastigmine,52 and galantamine53 showed improved psychosis and cognition in patients with PD, but were associated with poor tolerance and exacerbation of hallucinations. Recent small controlled trials of donepezil54,55 and one large multi-site trial of rivastigmine56 show improved cognitive test performance in acetylcholinesterase-treated patients compared to placebo, including selective improvements in memory.55 Cholinesterase inhibitors can aggravate parkinsonism, especially tremor, although some studies demonstrate improved motor function.55 Other cognitive enhancing agents, eg, memantine, in PD-related psychosis or dementia have not been studied, but some patients benefit cognitively from memantine in anecdotal experience.

 

Antipsychotics

Antipsychotics are indicated when other efforts to treat psychosis or agitation have failed or if antiparkinsonian medications cannot be reduced without sacrificing motor function. Importantly, they enable increases in antiparkinsonian medications. Since “typical” antipsychotics block dopamine D2 receptors and lead to increased parkinsonism, only “atypical” antipsychotics with a low potential for inducing parkinsonism (rigidity, bradykinesia, and tremor) are used in PD. Among those currently available (clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole), only quetiapine and clozapine are consistently recommended.  

Clozapine is currently the gold standard of antipsychotic agents in PD given its demonstrated safety and efficacy in controlled trials without worsening parkinsonian symptoms.57-59  The starting dose is usually 6.25–12.5 mg at night. Sedation or confusion can occur at low doses in this fragile population and most patients respond to <50 mg/day, though some require higher doses or an additional low dose in the mornings. The most common side effects are sedation, orthostasis, confusion, and drooling. Motor fluctuations worsen in some patients, but dystonia, dyskinesias, and tremor can improve.60,61 Weekly phlebotomy is required to monitor for potential agranulocytosis. Any inconvenience of this is offset by therapeutic benefits.  

Quetiapine is a common first choice because it can be used without the risk of agranulocytosis and weekly blood monitoring. However, quetiapine has not been subject to controlled trials. Its safety and efficacy profile in open-label studies is favorable,62 but inadequate symptom control or increased parkinsonism or motor fluctuations can occur.  Initial doses range from 6.25–25 mg, usually at night.  Lower doses are used initially because patients with hypotension or orthostasis may not tolerate higher doses.  The mean effective dose range in PD is usually 50–75 mg/day, but some patients tolerate and require up to 400 mg/day.63 Sedation and confusion are common side effects, but a recent open-label study showed improved cognitive functioning on quetiapine.63

Effects of aripiprazole on psychosis in PD are varied, and some patients have worse motor function.64,65 Initial open-label studies of olanzapine were favorable in terms of effectiveness and safety,63 but this was not shown in controlled trials.66,67 Risperidone is an effective antipsychotic, but is poorly tolerated in PD, even at doses <1 mg/day.68 The pharmacologic profile of ziprasidone suggests that it will be poorly tolerated from the standpoint of motor symptoms in PD patients.70 Reports on its use in PD patients are varied, including favorable outcomes as well NMS.71-73

 

Acute Management

Psychiatrists are often asked to manage acute agitation in PD patients.  Then, the general steps in Table 3 should be followed, but some more emergently than others. The acute setting is extremely challenging because the mental and motor state is even more unstable compared to the usual baseline, there are often active medical issues, and the medication regimen is often complex.74 Benzodiazepines (intramuscular or oral) are recommended for severe acute agitation that presents a danger to the patient or others; antipsychotics may not be as readily effective, although quetiapine has been used satisfactorily.74 Typical antipsychotics, namely haloperidol, which is used to treat agitation or delirium in non-PD patients, are not recommended as they induce severe parkinsonism.  This can result in medical complications such as deep venous thrombosis, aspiration pneumonia, decubiti, and fractures. Odansentron, a serotonin 5-HT3 blocker, can be given intravenously, intramuscularly, or orally and can be useful in emergency situations without exacerbating parkinsonism.29 Since many PD patients with severe agitation are managed on psychiatric or long-term care units, it is important for staff and clinicians to be aware of the potential for a NMS-like condition. This can occur with antipsychotic exposure, after withdrawal of antiparkinsonian medications, or spontaneously.75 The usual signs of NMS, rigidity, altered consciousness, elevated creatine kinase, hyperpyrexia, and autonomic instability, can be difficult to identify in PD patients with psychosis and acute agitation, who have some of these symptoms at baseline, especially if there is an intercurrent infection. 

 

Conclusion

Patients with advanced PD, who are already challenging to manage from a motor perspective, often develop psychosis, which can be accompanied by multiple other neuropsychiatric co-morbidities, including dementia, mood disorders, behavioral disturbances, medical illnesses, and adverse medication effects.  Assessment and treatment of PD-related psychosis requires careful attention to the multiple factors that contribute to its development and overall morbidity. Early recognition of psychosis, patient and caregiver education, elimination or modification of risk factors, and thoughtful use of antiparkinsonian and other psychoactive medications are integral to treatment. Since treatment of psychiatric comorbidities reduces burdens of the disease, clinicians should screen patients regularly for psychotic and other neuropsychiatric symptoms. PP

 

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