Rajesh Pahwa, MDRajesh Pahwa, MD
Neuropsychiatric manifestations represent a core feature of Parkinson disease (PD), from the prediagnostic phase to end-stage disease. Parkinson disease psychosis (PDP) is thought to be a result of an increase in the numbers of 5-HT2A receptors and dopaminergic hyperactivity. However, dopamine agonist (DA) medications like levodopa (L-dopa) that help reduce muscle rigidity and tremors can also trigger psychosis, marked by hallucinations and delusions. The clinical approach for treating PDP traditionally relies on initially reducing the dopaminergic agent and considering an add-on therapy for psychiatric symptom management.

Co-occurring psychiatric conditions in PD are common, and despite having considerable impact on patient quality of life (QOL), they remain underrecognized. Multiple scales have been developed in the clinical and research settings to help physicians assess symptoms like hallucinations, delirium, and psychosis. There is increasing evidence for pharmacological and nonpharmacological treatment options for depression, but the evidence for treatment of other neuropsychiatric features is much less robust.1 PDP has been reported to affect up to 60% of patients over their lifetime, and this risk increases with age and larger doses of DA medications.2 PDP also is associated with poor prognosis and usually entails greater caretaker burden, mortality, and increasing rates of nursing home placement.

Definition and formal criteria for PDP as a distinct disease entity have been established. PDP symptoms are believed to progress and can include hallucinations involving all 5 senses (most commonly, sight), illusions, and delusions. The progression is such that symptoms that are merely bothersome at an early stage will likely become more severe, varied, and troublesome as the disease progresses. PDP and impulse control disorders are reported to be associated with DA intake3 and are included in the behavioral spectrum of nonmotor symptoms of PD.

“Once a patient starts having psychosis symptoms, they will progress,” said Rajesh Pahwa, MD, Laverne & Joyce Rider Professor of Neurology at the University of Kansas Medical Center. “Clinicians should closely monitor patients and treat as the symptoms start causing problems for the patient or caregiver.”

Pharmacological Treatment

Onset of chronic PDP or transition from an acute to chronic state of PDP should prompt an evaluation of current therapies and a systematic reduction of those therapies in the following order: anticholinergic agents, selegiline, amantadine, DAs, catechol-O-methyltransferase inhibitors, and levodopa.4 If this strategy does not improve psychosis symptoms, physicians should consider use of cholinesterase inhibitors (eg, rivastigmine 6-12 mg/2-3 days, donepezil 5-10 mg daily, or galantamine 4-32 mg/2-3 days) or antipsychotic medication (clozapine 12.5-62.5 mg daily or quetiapine 12.5-75 mg daily).

The use of atypical antipsychotics in PD has been associated with a statistically significant risk of mortality.4 As an atypical antipsychotic, clozapine is slightly stronger than quetiapine but is associated with an increased risk for agranulocytosis, with an estimated prevalence of 1% to 2%.4 Quetiapine, a dibenzothiazepine derivative structurally related to clozapine, is the weakest atypical antipsychotic and thus has a lower risk of mortality. In a study comparing the efficacy of clozapine and quetiapine, Merims and colleagues5 found an overall trend for clozapine over quetiapine in controlling hallucinations and reducing delusions, but the high incidence of agranulocytosis with clozapine suggests a limitation in its use.

Other atypical antipsychotics have shown unreliable efficacy or unacceptable reductions in motor function. There is no evidence of efficacy for olanzapine in treating PDP, and it is associated with motor function deterioration.4 Risperidone has also been shown to worsen motor function and thus is not recommended for PDP.4 Melperone, an atypical antipsychotic of the butyrophenone chemical class, showed no benefit compared with placebo in a trial by Friedman.6

The only medication currently approved by the FDA for the treatment of PDP is pimavanserin (Nuplazid; Acadia), a potent and highly selective 5-HT2A inverse agonist without dopaminergic, adrenergic, histaminergic, or muscarinic affinity.7 These attributes make it unlikely to block postsynaptic DA and other off-target receptors. Pimavanserin’s mechanism of action is thought to decrease the excessive neurotransmission permitted by the 5-HT2A receptors, thereby reducing visual hallucinations in PDP.

Approved by the FDA in April 2016, pimavanserin is recommended as a daily 34-mg dosage and is indicated for the treatment of delusions and hallucinations in patients with PDP. In its phase 3 ACP-103-020 trial with an enrollment of 199 participants, pimavanserin was shown to decrease delusions by 41% and hallucinations by 34% compared with 21% and 18%, respectively, in the placebo group.8 Improvement in hallucinations and delusions was statistically significant on the Scale for the Assessment of Positive Symptoms global ratings. Researchers also found that treatment with pimavanserin did not worsen motor symptoms.8

Pimavanserin is not approved for the treatment of patients with dementia-related psychosis that is unrelated to the hallucinations and delusions associated with PDP, thereby creating a challenge when treating older patients with PD, who are more likely to have dementia. However, the results of a recent efficacy analysis of the phase 3 HARMONY study revealed that pimavanserin statistically significantly reduced the risk for relapse of dementia-related psychosis.9

The drug should be avoided in patients with a history of cardiac arrhythmias, symptomatic bradycardia, hypokalemia, hypomagnesemia, and QT prolongation or in combination with other medica- tions known to prolong the QT interval, including Class 1A or Class 3 antiarrhythmics. In clinical trials, pimavanserin has been shown to be well tolerated; its adverse effect profile includes urinary tract infections (UTIs), peripheral edema, hallucinations, confusion, nausea, and headaches.8

“As the symptoms often begin gradually, and if a patient is seen in clinic and has hallucinations occasionally and the patient has insight about them that they are not real, my approach is to monitor the patients,” said Pahwa, who is also chief of the Parkinson and Movement Disorder Division and director of the Parkinson Foundation Center of Excellence at the University of Kansas Medical Center. “If the patient calls before their next appointment and says their hallucinations are worse or bothersome, I check to make sure no new medications, such as narcotic pain medications, were added and check routine labs and [urinalysis] to make sure they don’t have a UTI or dehydration. If the patient [does have disease-related] delusions, we start pimavanserin.”

Compared with atypical antipsychotics to manage PDP that may cause adverse events such as worsened motor symptoms and orthostatic hypotension, pimavanserin is the preferred option for most patients based on its demonstrated clinical efficacy and safety.10

“If possible, I might reduce medications with anticholinergic properties [if they are taking them], reduce or eliminate amantadine, and reduce dopamine agonists,” Pahwa said. “If reducing medication does not reduce hallucination, I add pimavanserin.”

Recent findings presented at the American Academy of Neurology Annual Meeting held May 4-10, 2019, in Philadelphia, Pennsylvania, demonstrated that among individuals with PDP or Lewy body dementia, there were no significant differences in efficacy with pimavanserin or quetiapine in time to medication discontinuation, mortality, or psychosis improvement.11

“Pimavanserin is the only approved medication for PDP. Since it was approved based on [results from] 1 study, clinicians often feel that there are not enough data available for its efficacy,” Pahwa said.

Alternative Treatment Options

Enhancement of serotonergic neurotransmission and mesocorticolimbic pathway activation via electroconvulsive therapy (ECT) may have an antipsychotic and antidepressant effect in PD.4 Beneficial effects of ECT have been reported, with Calderón-Fajardo and colleagues noting an improvement in measures of motor and nonmotor function on different scales with use of ECT in 29 drug-refractory PD patients with psychiatric symptoms, including 12 patients with psychosis and depression.12 Issues related to safety and tolerability of ECT have not been reported; it’s important to note that studies to date have only been performed in small sample sizes and have not been blinded, begging the need for larger, sham-controlled studies.

The potential of deep brain stimulation (DBS) to treat psychiatric disorders has shown promise in conditions such as obsessive compulsive disorder and major depressive disorder; however, evidence of the effect of DBS in PDP is lacking.4 Studies have identified a variable positive and negative impact on psychiatric symptoms following DBS in PD, with some reporting worsening of or the emergence of new symptoms and others reporting improvements, namely in mood-related conditions.13 These findings, while inconclusive for patients with PDP, stress the importance of patient selection for DBS, as prior history of neuropsychiatric disorders appears to have an impact on outcomes.13

Results from preclinical and preliminary studies also suggest that cannabidiol (CBD) has therapeutic potential for nonmotor symp- toms of PD.14 The multifaceted mechanism of action as an agonist of 5-HT1A, partial agonist of CB1 and CB2 receptors, and antagonist of the G-protein–coupled receptor GPR55 reverses the iron-induced epigenetic modification of mitochondrial DNA and the reduction of succinate dehydrogenase activity and decreases the levels of the pro-inflammatory cytokines IL-1β, TNF-α, IFN-β, IFN-γ, IL-17, and IL-6—all of which decrease pro-inflammatory mediators resulting in neuroprotective, anxiolytic, and antipsychotic effects.14

“Several in vitro experiments have demonstrated promising neuro- protective effects of CBD in PD models. In one of these models, using PC12 and SH-SY5Y cells treated with MPP+ [1-methyl-4-phenylpyridinium], CBD increased cell viability, differentiation, and the expression of axonal [GAP-43] and synaptic [synaptophysin and synapsin I] proteins,” Ferreria-Junior and colleagues wrote,15 while acknowledging the paucity of studies that have addressed the biological bases for the purported effects of CBD on PD. “Double-blind, placebo-controlled, randomized trials with larger samples of patients with PD are needed to elucidate the possible effectiveness and mechanisms involved in the therapeutic potential of CBD in this movement disorder. This will also include the putative effects of CBD in preventing L-dopa–induced severe [adverse] effects and preventing PD progression.”

The endocannabinoid system serves as an important filter of excitatory, inhibitory, and modulatory inputs that act at the midbrain and terminal regions to orchestrate DA neurotransmission by controlling DA cell body firing patterns, terminal release, and effects on postsynaptic sites in the striatum.16 Beneficial effects of CBD administration have been observed prior to or immediately after induction of PD-like symptoms in animal studies, which may suggest a preventive role rather than a therapeutic one.14 In an early open-label pilot study to evaluate the efficacy of CBD on nonmotor symptoms of PD in 6 patients with PDP, psychotic symptoms significantly decreased under CBD treatment, as evaluated by the brief psychiatric rating scale and the Parkinson psychosis questionnaire.17

Pressing Needs

With PD and psychosis residing on what may be considered opposite ends of the DA spectrum, the complex interaction between the two presents physicians, patients, and caregivers with the difficult task of striking a balance between physical and emotional stability.

Despite estimates that the prevalence of PD will more than double by 2060, training in PD-specific mental health care is not standard in most programs, and the need for subspecialty-trained mental health care providers will only increase over time with the aging population. With limits on the extension of mental health care into existing models of integrated or multidisciplinary care, specialty mental health care is not routinely available, accessible, or integrated in most neurology practices.18

Psychiatric comorbidities prevalent in the majority of patients with PD are associated with more disease severity, impaired QOL, and increased use of health care resources, with longer hospital stays and rehospitalizations adding to the total cost burden. A multidisciplinary approach to managing PDP is crucial to improving the overall outcome and the health-related QOL of these patients and their caregivers.19 Future research should utilize clinical data and employ longitudinal designs to evaluate outcomes among patients with PDP and comorbid depression and other neuropsychiatric conditions.
REFERENCES
1. Nagy A, Schrag A. Neuropsychiatric aspects of Parkinson’s disease. J Neural Transm. 2019;126(7):889-896. doi: 10.1007/s00702-019-02019-7.
2. Forsaa EB, Larsen JP, Wentzel-Larsen T, et al. A 12-year population-based study of psychosis in Parkinson disease. Arch Neurol. 2010;67(8):996-1001. doi: 10.1001/archneurol.2010.166.
3. Weintraub D, David AS, Evans AH, Grant JE, Stacy M. Clinical spectrum of impulse control disorders in Parkinson's disease. Mov Disord. 2015;30(2):121-127. doi: 10.1002/mds.26016.
4. Taddei RN, Cankaya S, Dhaliwal S, Chaudhuri KR. Management of psychosis in Parkinson's disease: emphasizing clinical subtypes and pathophysiological mechanisms of the condition. Parkinsons Dis. 2017;2017:3256542. doi: 10.1155/2017/3256542.
5. Merims D, Balas M, Peretz C, Shabtai H, Giladi N. Rater-blinded, prospective comparison: quetiapine versus clozapine for Parkinson's disease psychosis. Clin Neuropharmacol. 2006;29(6):331-337. doi 10.1097/01.WNF.0000236769.31279.19.
6. Friedman JH. Melperone is ineffective in treating Parkinson's disease psychosis. Mov Disord. 2012;27(6):803-804. doi: 10.1002/mds.24942.
7. Meadowcraft LM, Tsurutis V, Morrisette T. Pimavanserin for treatment of hallucinations and delusions associated with Parkinson disease psychosis. Ann Long Term Care. 2016;25(3):43-48.
8. A Study of the Safety and Efficacy of Pimavanserin in Patients With Parkinson's Disease Psychosis. clinicaltrials.gov/ct2/show/NCT01174004. Updated March 26, 2014. Accessed August 26, 2019.
9. Acadia Pharmaceuticals announces pivotal phase 3 HARMONY trial stopped early for positive efficacy as pimavanserin meets the primary endpoint in patients with dementia-related psychosis [news release]. San Diego, CA: Acadia Pharmaceuticals Inc; September 9, 201 biospace.com/article/releases/acadia-pharmaceuticals-announces-pivotal-phase-3-harmony-trial-stopped-early-for-positive-efficacy-as-pimavanserin-meets-the-primary-endpoint-in-patients-with-dementia-related-psychosis/. Accessed September 10, 2019.
10. Lyons KE, Pahwa R, Hermanowicz N, Davis T, Pagan F, Isaacson S. Changing the treatment paradigm for Parkinson’s disease psychosis with pimavanserin. Expert Rev Clin Pharmacol. 2019;12(7):681-691. doi: 1080/17512433.2019.1623669.
11. Horn S, Dahodwala N. Pimavanserin versus quetiapine for the treatment of psychosis in Parkinson’s disease and dementia with Lewy bodies. Presented at: 2019 American Academy of Neurology Annual Meeting; May 4-10, 2019. Philadelphia, Pennsylvania. n.neurology.org/content/92/15_Supplement/P2.8-037.
12. Calderón-Fajardo H, Cervantes-Arriaga A, Llorens-Arenas R, Ramírez-Bermudez J, Ruiz-Chow Á, Rodríguez-Violante M. Electroconvulsive therapy in Parkinson's disease. Arq Neuropsiquiatr. 2015;73(10):856-860. doi: 10.1590/0004-282X20150131.
13. Accolla EA, Pollo C. Mood effects after deep brain stimulation for Parkinson's disease: an update. Front Neurol. 2019;10:617. doi: 10.3389/fneur.2019.00617.
14. Peres FF, Lima AC, Hallak JEC, Crippa JA, Silva RH, Abílio VC. Cannabidiol as a promising strategy to treat and prevent movement disorders? Front Pharmacol. 2018;9:482. doi: 10.3389/fphar.2018.00482.
15. Ferreira-Junior NC, Campos AC, Guimarães FS, et al. Biological bases for a possible effect of cannabidiol in Parkinson’s disease [published online July 15, 2019]. Braz J Psychiatry. doi: 10.1590/1516-4446-2019-0460.
16. Covey DP, Mateo Y, Sulzer D, Cheer JF, Lovinger DM. Endocannabinoid modulation of dopamine neurotransmission. Neuropharmacology. 2017;124(15):52-61. doi: 10.1016/j.neuropharm.2017.04.033.
17. Zuardi AW, Crippa J, Hallak JEC, et al. Cannabidiol for the treatment of psychosis in Parkinson’s disease. J Psychopharmacol. 2009;23(8):979-983. doi: 10.1177/0269881108096519.
18. Pontone GM, Dissanayaka N, Dobkin RD, et al. Integration and extension of specialty mental healthcare services to community practice in Parkinson Disease. Am J Geriatr Psychiatry. 2019;27(7):712-719. doi: 10.1016/j.jagp.2019.03.005.
19. Imran S, Patel RS, Onyeaka HK, et al. Comorbid depression and psychosis in Parkinson's disease: A report of 62,783 hospitalizations in the United States. Cureus. 2019;11(7):e5227. doi: 10.7759/cureus.5227.