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Pimavanserin gets a lot of attention due to its niche of treating psychosis in Parkinson’s disease. Is pimavanserin actually better than what you have been using—which are, according to a 2017 review and 2019 Canadian guidelines, quetiapine and clozapine, right?
Hi! Jim Phelps here for the Psychopharmacology Institute. Did you know that psychosis in Parkinson’s is basically iatrogenic? Really? Right. Before levodopa, depression and other psychiatric disorders were described in people with Parkinson’s disease, but psychosis was rare. So, it makes sense that even now, psychosis is rare in untreated Parkinson’s disease. For patients who are taking prodopaminergic medications, the incidence of psychosis is around 30% and in some studies up to 50%.
Is pimavanserin the solution? Well, that depends on where you look and how you look at it. What we need is a meta-analysis. And here’s one by Mansuri and colleagues. They found 2 published and 3 unpublished trials. All were company sponsored. Only the positive ones were published. But in meta-analysis of all 5, pimavanserin did outperform placebo. But is it better than quetiapine or clozapine? Ah, pity, there are no head-to-head studies. So, we need a network meta-analysis, and here is one by Yunusa and colleagues.
Before we look at the comparison outcomes, a key question is: Is it Parkinson’s psychosis or delirium? The usual differentiating factors apply—acute vs insidious, impaired consciousness vs clear sensorium. But visual hallucinations are seen in both. As for thought process, it’s disorganization and inattention in delirium vs delusions, often complex delusions with loss of insight in Parkinson’s psychosis. So, once you’ve established that, uh-oh, it’s Parkinson’s psychosis all right, what are the treatment options? It’s not straight to pimavanserin. A 2000 review breaks down 6 steps. You won’t be surprised by the first 3, which are basic dementia treatment ingredients. First, general measures like reestablishing circadian rhythm and ensuring hearing and vision. Second, look for triggers—infection, dehydration, cardiac insufficiency, oxygenation problems. And third, eliminate nonessential medications, particularly anticholinergic, antiglutamatergic, and sedating drugs.
The fourth, which is also obvious but trickier, is the reduction of antiparkinsonian medications. A 2017 review suggests the following order: Anticholinergic agents—selegiline, amantadine; dopamine agonists; COMT inhibitors—that’s entacapone and opicapone; and only lastly, L-DOPA. Step 5, if there’s cognitive impairment as well as psychosis, you might consider a cholinesterase inhibitor. And then finally, step 6, antipsychotics.
And so, now to the network meta-analysis regarding which one is best—quetiapine, clozapine, or pimavanserin. The authors’ conclusions from that network meta-analysis is that they all work and none clearly more than another. Clozapine clearly had more side-effect dropouts, quetiapine more cognitive impairment, and that’s it. Cost is not mentioned there, so I looked quickly. Pimavanserin is about $4,500 a month, although there are discount programs.
In summary, any of those 3 medications is just as worth considering as the rest, and there are obvious differences between them, including cost. Don’t forget all the other preceding steps. And for more on that, the 2017 review, which can be found in the related references, has more detail on each of those steps.
Abstract
Comparative Efficacy, Safety, and Acceptability of Pimavanserin and Other Atypical Antipsychotics for Parkinson’s Disease Psychosis: Systematic Review and Network Meta-Analysis
Ismaeel Yunusa, Nazia Rashid, Roxanna Seyedin, Deepika Paratane, Krithika Rajagopalan
Background: The current comparative efficacy, safety, and acceptability of atypical antipsychotics (AAPs) in treating Parkinson’s Disease Psychosis (PDP) are not entirely understood.
Objective: To evaluate comparative efficacy, safety, and acceptability of AAPs in patients with PDP.
Methods: We conducted a systematic review and a network meta-analysis to compare the efficacy, safety, and acceptability of pimavanserin, quetiapine, olanzapine, clozapine, ziprasidone, and risperidone. We estimated relative standardized mean differences (SMDs) for continuous outcomes and odds ratios (OR) for binary outcomes, with their respective 95% confidence intervals (CIs).
Results: We included 19 unique studies evaluating AAPs in a total of 1,242 persons with PDP. Based on Clinical Global Impression Scale for Severity, pimavanserin (SMD, -4.81; 95% CI, -5.39, -4.24) and clozapine (SMD, -4.25; 95% CI, -5.24, -3.26) significantly improved symptoms compared with placebo. Also, compared to placebo, pimavanserin (OR, 1.16; 95% CI, 1.07, 1.24) significantly improved psychotic symptoms based on Scale for Assessment of Positive Symptoms for Parkinson’s Disease Psychosis/Hallucinations and Delusions scores. In comparison to placebo, clozapine (SMD, -0.69; 95% CI, -1.35, -0.02), pimavanserin (SMD, -0.01; 95% CI, -0.56, 0.53), and quetiapine (SMD, 0.00; 95% CI, -0.68, 0.69) did not impair motor function per Unified Parkinson’s Disease Rating scale. Based on Mini-Mental State Examination scale, quetiapine (SMD, 0.60; 95% CI, 0.07, 1.14) significantly impaired cognition compared to placebo.
Conclusions: In patients with PDP, pimavanserin and clozapine demonstrated significant improvement in psychosis without affecting motor function. With quetiapine being associated with a significant decline in cognition and despite not impairing motor function, our findings suggest that it should be avoided in patients with PDP and reduced cognitive abilities.
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Reference
Yunusa, I., Rashid, N., Seyedin, R., Paratane, D., & Rajagopalan, K. (2023). Comparative efficacy, safety, and acceptability of pimavanserin and other atypical antipsychotics for Parkinson’s Disease psychosis: systematic review and network meta-analysis. Journal of Geriatric Psychiatry and Neurology, 08919887231154933.
Related References
- Factor, S. A., Molho, E. S., Podskalny, G. D., & Brown, D. (1995). Parkinson’s disease: drug-induced psychiatric states. Advances in Neurology, 65, 115-138.
- Taddei, R. N., Cankaya, S., Dhaliwal, S., & Chaudhuri, K. (2017). Management of psychosis in Parkinson’s disease: emphasizing clinical subtypes and pathophysiological mechanisms of the condition. Parkinson’s Disease, 2017.
- Grimes, D., Fitzpatrick, M., Gordon, J., Miyasaki, J., Fon, E. A., Schlossmacher, M., … & Hutton, B. (2019). Canadian guideline for Parkinson disease. CMAJ, 191(36), E989-E1004.
- Mansuri, Z., Reddy, A., Vadukapuram, R., Trivedi, C., & Amara, A. (2022). Pimavanserin in the treatment of Parkinson’s Disease psychosis: Meta-analysis and meta-regression of randomized clinical trials. Innovations in Clinical Neuroscience, 19(1-3), 46.
