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Table of Contents
REVIEW ARTICLES
Year : 2019  |  Volume : 2  |  Issue : 3  |  Page : 83-90

Approach to the management of psychosis in Parkinson’s disease


Department of Neurology, MedStar Georgetown University Hospital, Washington, DC, USA

Date of Submission22-Oct-2019
Date of Decision28-Oct-2019
Date of Acceptance13-Nov-2019
Date of Web Publication04-Dec-2019

Correspondence Address:
Abhishek Lenka
Department of Neurology, MedStar Georgetown University Hospital, Washington, DC 20007.
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AOMD.AOMD_27_19

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  Abstract 

Psychosis is a common and often debilitating non-motor symptom of Parkinson’s disease (PD). It typically manifests in the form of well-formed visual hallucinations and minor hallucinations, and, at times, can present with delusions and nonvisual hallucinations. Psychosis is associated with many adverse outcomes in PD, and for that reason, it is essential to recognize and treat the symptoms early. The objective of this review article is to highlight the phenomenology, diagnosis, and pathophysiology of PD-associated psychosis (PD-P) and discuss a step-by-step approach to its management. One of the critical steps in managing PD-P is the identification of potential non-PD causes of psychosis, which often require conservative measures. If no secondary causes are identified, pharmacotherapy should be considered. Role of several drugs including pimavanserin (the only FDA-approved agent for the treatment of PD-P), atypical antipsychotics such as quetiapine and clozapine, and cholinesterase inhibitors such as rivastigmine and donepezil are discussed in this review. In addition, we also highlight the potential role of noninvasive brain stimulation (electroconvulsive therapy and transcranial magnetic stimulation) for the treatment of medication-refractory psychosis.

Keywords: Antipsychotics, Parkinson’s disease, pimavanserin, psychosis, visual hallucinations


How to cite this article:
Lenka A, Gomathinayagam V, Bahroo L. Approach to the management of psychosis in Parkinson’s disease. Ann Mov Disord 2019;2:83-90

How to cite this URL:
Lenka A, Gomathinayagam V, Bahroo L. Approach to the management of psychosis in Parkinson’s disease. Ann Mov Disord [serial online] 2019 [cited 2020 Apr 10];2:83-90. Available from: http://www.aomd.in/text.asp?2019/2/3/83/272289




  Introduction Top


Psychosis is one of the debilitating non-motor symptoms of Parkinson’s disease (PD). The prevalence of psychosis in PD (PD-P) may range from 16% to 75%.[1] PD-P commonly manifests through minor hallucinations (MH) and/or well-structured visual hallucinations (VH).[2],[3] MH include a false sense of presence (presence hallucinations), a false sense of passage (passage hallucinations), and illusions.[2] Delusions and Non-visual hallucinations (e.g., auditory hallucinations, tactile hallucinations, olfactory hallucinations, gustatory hallucinations) are relatively uncommon and, when present, usually coexist with MH or VH.[4] Although the exact underlying mechanism is yet to be fully understood, previous cross-sectional as well as longitudinal studies have identified several risk factors for the development of PD-P. These risk factors include older age, higher stage of PD, greater disease severity, sleep disturbances such as excessive daytime sleepiness and rapid eye movement (REM) sleep behavior disorder (RBD), cognitive impairment, depression, and postural instability and gait difficulty (PIGD) phenotype of PD.[5],[6],[7] Although the exact reason remains elusive, certain genetic forms of PD, including those with mutation of the glucocerebrosidase (GBA) gene and the alpha-synuclein gene (SNCA), have a higher prevalence and earlier age of onset of psychiatric symptoms compared to patients with idiopathic PD.[8],[9] It is unclear if the pathogenesis and natural course of psychosis in genetic forms of PD are different from that in sporadic form of PD. In addition to its robust association with some of the debilitating non-motor symptoms such as cognitive impairment and RBD, several studies have linked psychosis to a higher risk of suicidal ideations in patients with PD.[10],[11] Moreover, psychosis is associated with higher rates of mortality,[12],[13] nursing home placements,[14] health-care utilization,[15] and more significant caregiver burden.[16]

Considering the aforementioned adverse outcomes associated with PD-P, timely diagnosis and optimal management of this burdening non-motor symptom are crucial. Management of PD-P, however, is challenging as the diagnosis is not always straightforward, the therapeutic options are often limited, and it often necessitates a multidisciplinary approach. In this review, we describe a comprehensive approach to the diagnosis and treatment of PD-P.


  Phenomenology of Parkinson’s disease-associated psychosis and its diagnosis Top


As mentioned above, there is a marked variation in the reported prevalence of psychosis in PD, that is, 16%–75%. Such variation has been primarily attributed to inconsistencies across studies in the diagnosis of PD-P. Another plausible reason behind this variation could be the place of assessment, that is, community-based studies or clinic-based studies. Several previous studies have used section-1 of the unified Parkinson disease rating scale (UPDRS) to document the behavioral symptoms, including psychosis, whereas several other studies have used the neuropsychiatry inventory (NPI). In addition, recognition of the MH as part of the phenomenology of PD-P has resulted in a higher prevalence of PD-P.[17] Considering such inconsistencies, the workgroup of the National Institutes of Neurological Disorders and Stroke (NINDS) and National Institutes of Mental Health (NIMH) proposed diagnostic criteria for PD-P [Table 1].[18] As per these criteria, continuous presence for 1 month or recurrent emergence of illusions or a false sense of presence or hallucinations or delusions are considered as the characteristic symptoms of PD-P. For the diagnosis of PD-P, any of aforementioned symptoms must have occurred after the diagnosis of PD and other disease that could contribute toward the psychotic symptom ( Lewy body dementia More Details, psychiatric disorders such as schizophrenia, schizoaffective disorder, delusional disorder, or mood disorder with psychotic features, or a general medical condition including delirium) should be excluded.
Table 1: NINDS–NIMH diagnostic criteria for the diagnosis of psychosis associated with Parkinson’s disease

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  Pathogenesis of psychosis in Parkinson’s disease Top


Several studies over the last decade have provided valuable insights into the potential pathogenesis of PD-P.[3] However, the exact neurobiological underpinnings have not been fully understood. On the basis of the results of the neuroimaging studies, two mechanisms have been put forth. As per one of the theories, PD patients with VH have an aberrant top-to-bottom visual processing system, which dominates the conventional bottom-to-top visual processing system. This is evident from the fact that the molecular imaging studies documented lower glucose metabolism or lower blood flow in the visual cortex and increased glucose metabolism or increased blood flow in frontal areas of the brain.[19] Moreover, gray matter volume reduction in the brain regions corresponding to both dorsal and ventral visual pathways is a consistent finding across the volumetry-based studies.[19]

The other theory emphasizes the interplay of three neural networks, that is, default mode network (DMN), ventral attention network (VAN), and dorsal attention network (DAN).[20] DMN is a network of brain regions that are active when a person is not engaged in any mental task. Contrary to the task-negative nature of the DMN, the VAN represents a group of brain regions that are active during stimulus-driven activities. Shifting the attention toward an externally focused goal-directed task activates the DAN with concomitant deactivation of the DMN.[21] Perceptual errors may occur in the background of abnormal interaction between the DMN or VAN, and in such conditions, a normal DAN would rectify the errors. A growing body of evidence suggests that abnormalities in these three networks are strongly associated with the emergence of psychosis.

The large-scale neural network abnormalities could stem from neurotransmitter imbalance. For example, previous work on healthy individuals has revealed that striatal dopamine levels correlated with the activity of the DMN.[22] Hence, in patients with advanced PD, dopamine, acetylcholine, and serotonin are possibly associated with impaired signaling across the attentional networks. The association of long-term use of dopaminergic agents and anticholinergic agents with the emergence of psychosis supports the putative role of the imbalance of dopamine and acetylcholine transmission in the pathogenesis of PD-P. Similarly, strong evidence for the association of serotonin with hallucinations in major psychiatric diseases such as schizophrenia stems the possibility that faulty serotonin transmission is also associated with hallucinations in PD.[23] Additional research exploring the exact effect of these neurotransmitters on the attentional networks has the potential to elucidate the pathogenesis of PD-P further.


  Treatment of psychosis in Parkinson’s disease Top


One of the critical steps in the management of psychosis in PD is to determine whether the psychotic symptoms are genuinely related to PD or other causes. It is crucial to delineate psychotic symptoms secondary to pathologies other than PD promptly. Acute or subacute onset of psychosis in PD should be considered as a red flag. Some of the commonly encountered medical comorbidities which can trigger psychotic symptoms in PD include fever, urinary tract infections, dehydration, electrolyte imbalance, and recent changes in medication. Considering the fact that older PD patients are at a higher risk for falls, subdural hematoma should be included in the differential diagnoses while assessing PD patients with acute or subacute psychosis. Physicians should also be vigilant about two crucial factors, that is, a recent change in the sleep-wake cycle and abnormalities or alterations in sensory inputs (loss of hearing aids, prescription glasses) [Table 2].
Table 2: Summary of the potential causes of acute psychosis and the suggested investigations

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One of the significant risk factors for the emergence of psychosis in PD is the long-term use of certain anti-parkinsonian medications. Trihexyphenidyl hydrochloride, which has been prescribed to a subset of patients with tremor dominant PD, and amantadine, which has been regarded as an anti-dyskinetic medication, have a strong association with the genesis of psychosis. In addition, dopamine receptor agonists such as pramipexole and ropinirole, and monoamine oxidase-B (MAO-B) inhibitors such as selegiline and rasagiline have also been commonly associated with psychosis in PD. Hence, the treatment chart of patients with new-onset psychosis should be carefully reviewed to see addition or augmentation of the dose of any of the aforementioned anti-parkinsonian medications. If appropriate, modification in the dosage and/or replacement of the offending medication with other classes of medication should be considered. However, there are no consensus or guidelines regarding the order in which the dose of these psychoactive medications should be reduced or discontinued. Several experts have advocated for reducing or discontinuing anticholinergics, amantadine, dopamine agonists, and MAO-B inhibitors, in that order, before down-titrating levodopa. Worsening of parkinsonian signs should be anticipated while tapering medications, often necessitating an augmentation in the dose or addition of different classes of medications. For example, if a patient on monotherapy with pramipexole 3mg/d develops psychosis, the dose should be reduced to the lowest tolerable dose, and the physician should consider adding a low dose of levodopa in order to maintain a steady level of total levodopa equivalent dose. Nevertheless, titration of these medications should be individualized based on other symptoms such as dyskinesias, autonomic disturbances, and other side effects of the medications.

In addition to the issues mentioned above, new-onset psychosis in patients who had undergone deep brain stimulation (DBS) warrants a careful review of the recent changes to the stimulation parameters. Hallucinations and manic episodes after DBS of the subthalamic nucleus are not uncommon.[24],[25],[26] A change in the site or the parameters of stimulation would be prudent if psychosis develops within a few days after electrode implantation or programming of the stimulation parameters.

If there are no apparent secondary causes of psychosis, and the symptoms are bothersome, pharmacotherapy should be offered to eligible patients [Figure 1].
Figure 1: Summary of the step-by-step approach to the management of psychosis in Parkinson’s disease. CBC = Complete blood count; COMT = Catechol-O-methyl transferase; DA = Dopamine; ECT = Electroconvulsive therapy; MAO-B = Monoamine oxidase inhibitor-B; PD = Parkinson’s disease; PD-P = Parkinson’s disease-associated psychosis; rTMS = Repetitive transcranial magnetic stimulation

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Pharmacotherapy for psychosis in Parkinson’s disease

Pimavanserin

Pimavanserin is a combined inverse agonist of the 5-HT2A and 5HT2C receptors. It is the only FDA-approved drug for the treatment of PD-P. Importantly, pimavanserin is the only antipsychotic medication that does not have dopamine blocking property. In a large randomized placebo-controlled clinical trial, treatment with pimavanserin resulted in a significant improvement in psychosis in patients with PD.[27] This 6-week multicenter trial compared the scores on the scale for assessment of positive symptoms (SAPS) adapted for PD (SAPS-PD) between 90 patients who received a placebo vs. 95 patients who received pimavanserin.[27] After 6 weeks, the latter group had a significant decrease in the SAPS-PD score as compared to the placebo group, without any significant adverse events or treatment-associated impairment of the motor functions. Moreover, pimavanserin resulted in a significant improvement in measures of nighttime sleep, daytime wakefulness, and caregiver burden. A prior study on 60 patients with PD-P also reported a significant improvement in the SAPS score after treatment with pimavanserin.[28] In a recently published evidence-based medicine review, commissioned by the international movement disorders society, pimavanserin was described as “clinically useful” for the treatment of psychosis in PD.[29] Long-term data demonstrating the efficacy and safety of pimavanserin will be published soon.

The recommended dose for pimavanserin is 34mg/d, and it can be taken with or without food. Although compared to placebo, pimavanserin was not associated with significant adverse events in the clinical trials, the current formulation is commercially available with a boxed warning as demented patients taking antipsychotics have increased overall mortality.[30] As pimavanserin is associated with prolongation of QT-interval, it should be ideally avoided in patients with known prolonged-QT interval and history of arrhythmias. Its concomitant use with other drugs associated with QT-prolongation should be avoided. Peripheral edema and confusion are the other rare side effects that the prescribers should be familiar with. Pimavanserin is hepatically metabolized by CYP3A4. Exposure to potent inhibitors such as ketoconazole should result in dose reduction to 10mg daily. Strong inducers should be monitored as they will reduce the efficacy of pimavanserin (FDA label for pimavanserin: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207318lbl.pdf).

Clozapine

Clozapine is one of the oldest second-generation antipsychotics, which is not usually associated with significant extrapyramidal symptoms. Several open-label studies and two placebo-controlled trials have reported the efficacy of clozapine in ameliorating the psychotic symptoms in PD.[31],[32],[33] In the PSYCLOPS (PSYchosis and CLOzapine in the treatment of  Parkinsonism More Details) trial on 60 patients with PD-P, clozapine (with a dose < 50mg/d) resulted in improvement in psychosis compared to placebo, without aggravating the parkinsonian symptoms. Interestingly, this study also reported the anti-tremor effect of clozapine.[32] Similar results, highlighting the efficacy of clozapine in reducing the psychotic symptoms in PD, were reported in another trial in France.[33]

On the basis of the aforementioned clinical trials, starting clozapine at a dose of 6.25mg/d and titrating it to up to 50mg/d is recommended for the treatment of PD-P. Although clozapine is useful for the treatment of PD-P without any extrapyramidal side effects, its association with a severe adverse reaction, that is, agranulocytosis, is concerning. Given the risk of agranulocytosis, frequent blood monitoring is required, and it often limits the use of clozapine. If the absolute neutrophil count drops to 1000, clozapine should be discontinued.

Quetiapine

The role of quetiapine in the treatment of PD-P remains controversial. Several open-label studies have reported a significant improvement in psychotic symptoms (in 80% of the patients) after treatment with quetiapine.[34] The magnitude of the improvement with quetiapine ranged from 26% to 36% and was reported to be clinically meaningful in all open-label studies.[25] However, three double-blind placebo-controlled trials did not find any significant benefit with quetiapine compared to placebo.[35],[36],[37] Interestingly, several experts found quetiapine clinically useful in their personal practice, and it is still being used for the treatment of PD-P.[38] In a study that compared the efficacy of clozapine (up to 50mg/d) and quetiapine (up to 150mg/d), the former was more effective in reducing the frequency of hallucinations and delusions.[39]

To summarize, although three double-blind placebo-controlled trials did not find quetiapine to be effective in reducing psychotic symptoms, a multitude of open-label studies and several experts have found quetiapine clinically useful. As it is not associated with any significant side effects (except QT prolongation), quetiapine is still considered necessary if pimavanserin is not commercially available and if patients are apprehensive about side effects of clozapine. In such scenarios, quetiapine can be started with a dose of 12.5mg/d and can be titrated up to 150mg/d. The commonly observed side effects include drowsiness and QT-prolongation.

Cholinesterase inhibitors

Donepezil and rivastigmine have been tried in several open-label studies and have yielded mixed results. In a case series on demented PD patients with hallucinations, rivastigmine was well-tolerated and was effective in improving the cognitive function as well as the behavioral symptoms, including hallucinations.[40] In an open-label study on 23 PD patients with cognitive impairment, 6-month therapy with rivastigmine (patch: 20 patients and oral: 3 patients) significantly improved the frequency and severity of hallucinations.[41] Interestingly, a recent study on patients with PD on pimavanserin reported that the efficacy of pimavanserin is more in patients with cognitive dysfunction, and concomitant use of cognitive-enhancing medications further enhances the effect of pimavanserin.[42] A number of case reports have reported improvement in psychotic symptoms after treatment with donepezil.[43],[44] Considering this, cholinesterase inhibitors should be an automatic choice with demented PD patients with hallucinations.

Switching from off-label antipsychotics to pimavanserin

Patients who are on off-label antipsychotics might require a switch to pimavanserin either because of inefficacy in ameliorating psychotic symptoms or because of the emergence of bothersome side effects. A recently published expert consensus recommends adding full strength of pimavanserin (34mg/d) to the continuing quetiapine dose for 4 weeks and continuing clozapine dose for 6 weeks, followed by tapering the antipsychotics in the following ways.[45]

*High-dose quetiapine (>100mg/d) should be reduced by 50% every week until reaching 12.5mg/d and then should be discontinued.

*Low-dose quetiapine (<100mg/d) should be reduced by 25% every week until reaching 12.5mg/d and then should be discontinued.

*High-dose clozapine (>100mg/d) should be reduced by 25mg every week until discontinued.

*Low-dose clozapine (<100mg/d) should be reduced by 6.25mg every week until discontinued.

While tapering the antipsychotics, if the efficacy for PD-P diminishes, the prescribers can return to the previous dose level, and the tapering should be attempted again in 1 week.

Non-pharmacological approaches

Electroconvulsive therapy

Electroconvulsive therapy (ECT) involves brief electrical stimulation of the brain under general anesthesia. It is one of the mainstay treatments for drug-resistant psychiatric disorders such as depression, bipolar disorder, and psychosis. Several studies have found ECT useful in alleviating the psychotic symptoms in PD. Usui et al.[46], in a study on eight patients with quetiapine resistant PD-P, reported a significant improvement in the SAPS score after ECT. Moreover, ECT also resulted in an improvement in motor symptoms. A prior study on five patients with PD-P had also yielded similar results.[47] A retrospective study revealed a significant improvement (nearly 50%) in the brief psychiatric rating scale (BPRS) as well as Hamilton depression rating scale after ECT in PD patients with psychosis and depression, respectively, suggesting that ECT could be promising in treating both psychosis and depression in PD.[48] In addition to the studies mentioned earlier, several other case reports have documented improvement in psychotic symptoms in PD after ECT.[49],[50],[51]

Although additional studies are warranted to explore the long-term effects of ECT on PD-P and other symptoms of PD, it is certainly useful in drug-resistant psychosis in PD. ECT appears promising because, in addition to the improvement of psychosis, it is also associated with the improvement of motor symptoms of PD. Hence, ECT should be strongly considered in patients who did not improve with pharmacological treatment (pimavanserin/quetiapine/clozapine/cholinesterase inhibitor) or developed bothersome adverse effects with the medications mentioned above.

Transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that is useful for the treatment of several movement disorders and psychiatric diseases.[52] A recent case report documented a significant improvement in complex VH in a patient with PD after 10-days of 1-Hz rTMS in the occipital cortex.[53] rTMS was effective in reducing hallucinations in several other non-parkinsonian disorders as well.[54],[55] As rTMS is noninvasive and is not associated with any serious adverse events, future trials are warranted to further assess its efficacy in the treatment of drug-resistant psychosis in PD.


  Conclusion Top


PD-P is one of the most debilitating NMS of PD, which results in significant psychosocial and financial burden on patients and caregivers. For all the PD patients with new psychosis, the neurologists should rule out underlying toxic/metabolic causes and abrupt changes in circadian rhythm. Although there are no clear guidelines, pimavanserin (34mg/d) can be a starting point for pharmacotherapy for PD-P as it is the only FDA-approved drug for PD-P, and it is not associated with any serious adverse effect. If ineffective or unavailable, either clozapine (up to 50mg/d) or quetiapine (slowly up to 150mg/d) should be considered. In that case, patients and caregivers should be clearly explained that although quetiapine is usually a safe medication, it may not be effective in reducing the psychotic symptoms in some patients. Similarly, the risk of agranulocytosis and the requirement of frequent blood monitoring should be explained in detail. In patients with coexisting dementia, cholinesterase inhibitors should be offered. As mentioned above, if pharmacotherapy fails in alleviating bothersome psychotic symptoms, ECT should come into the plan of care [Figure 1].

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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