Pimavanserin (Nuplazid): A Comprehensive Monograph on a Novel Dopamine-Sparing Antipsychotic

Introduction and Molecular Profile

Overview and Therapeutic Distinction

Pimavanserin is a first-in-class atypical antipsychotic agent that occupies a unique position in modern psychopharmacology. It is specifically indicated for the treatment of hallucinations and delusions associated with Parkinson's Disease Psychosis (PDP), a common and debilitating non-motor symptom of Parkinson's disease.[1] Marketed under the brand name NUPLAZID® and developed by ACADIA Pharmaceuticals, pimavanserin represents a significant therapeutic advancement.[1] Its introduction addresses a critical unmet need in neurology and psychiatry, offering a treatment for psychosis that does not exacerbate the underlying motor deficits of Parkinson's disease.

The central distinction of pimavanserin lies in its novel mechanism of action. It is the first and only antipsychotic approved by the U.S. Food and Drug Administration (FDA) that is devoid of dopamine D2 receptor blocking activity.[1] For decades, the management of psychosis in patients with Parkinson's disease was a clinical paradox: conventional antipsychotics, which antagonize D2 receptors, would control psychotic symptoms at the expense of worsening parkinsonism. Pimavanserin circumvents this issue, providing a targeted therapy that alleviates hallucinations and delusions without compromising motor function, thereby marking a paradigm shift in the management of PDP.[1]

Nomenclature, Identifiers, and Physicochemical Properties

To ensure unambiguous identification, pimavanserin is characterized by a comprehensive set of names and registry numbers established throughout its development and commercialization.

• Generic Name: Pimavanserin [1]
• Brand Name: NUPLAZID® [1]
• Synonyms/Research Codes: ACP-103, ACP 103, ACP103, Pimaserin [1]
• DrugBank ID: DB05316 [1]
• CAS Number: 706779-91-1 [8]
• FDA UNII: JZ963P0DIK [9]
• ATC Code: N05AX17 [9]

The progression from the research code ACP-103 to the generic name pimavanserin and finally to the marketed product NUPLAZID maps the drug's full lifecycle from a preclinical compound to a clinical therapeutic, providing a clear developmental context.[1] The physicochemical properties of the pimavanserin free base are summarized in Table 1.

Table 1: Summary of Physicochemical Properties of Pimavanserin

Property	Value	Source(s)
CAS Number	706779-91-1	8
Molecular Formula	C25​H34​FN3​O2​	8
Molecular Weight	427.55 g/mol	9
Physical Form	Solid	9
Color	Pale Yellow to Pale Orange	9
Melting Point	100-103°C	9
Predicted Boiling Point	604.2±55.0 °C	9
Predicted Density	1.15±0.1 g/cm3	9
Solubility	DMF: 33 mg/ml; DMSO: 33 mg/ml; Ethanol: 33 mg/ml; Methanol (Slightly); Ethanol:PBS (pH 7.2) (1:1): 0.5 mg/ml	8
SMILES	N(CC1=CC=C(F)C=C1)(C1CCN(C)CC1)C(NCC1=CC=C(OCC(C)C)C=C1)=O	9
InChIKey	RKEWSXXUOLRFBX-UHFFFAOYSA-N	8
Stability	≥ 4 years (under proper storage)	8

Chemical Structure and Formulation

The formal chemical name for pimavanserin is N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N'-[[4-(2-methylpropoxy)phenyl]methyl]-urea.[8] The commercially available product, NUPLAZID, is formulated with the tartrate salt of the active molecule, which has the chemical name urea, N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N'-[[4-(2- methylpropoxy)phenyl]methyl]-,(2R,3R)-2,3-dihydroxybutanedioate (2:1).[13] This formulation has a molecular weight of 1005.20 and is freely soluble in water.[13]

The selection of a tartrate salt is a deliberate pharmaceutical strategy. The pimavanserin free base exhibits limited aqueous solubility, as evidenced by its low solubility in a phosphate-buffered saline (PBS) solution.[8] Converting a poorly soluble molecule into a salt form is a standard and effective method in drug development to enhance aqueous solubility and dissolution rate. This improved solubility is critical for ensuring reliable and consistent absorption from the gastrointestinal tract following oral administration. Therefore, the tartrate salt formulation was a key step in creating a viable and effective oral dosage form suitable for its target elderly patient population.[13]

Preclinical and Clinical Pharmacology

Mechanism of Action: Selective 5-HT2A Receptor Inverse Agonism

Pimavanserin's therapeutic effect is primarily mediated through a unique combination of inverse agonist and antagonist activity at serotonin 5-hydroxytryptamine 2A (5−HT2A​) receptors.[1] This mechanism represents a fundamental departure from traditional antipsychotic therapy. Historically, antipsychotic efficacy was believed to be inextricably linked to dopamine D2 receptor blockade.[7] Pimavanserin's success clinically validates the serotonergic hypothesis of psychosis, particularly in the context of Parkinson's disease, demonstrating that psychosis can be effectively managed by modulating the serotonin system alone.

The concept of inverse agonism is central to its action. A traditional or "neutral" antagonist binds to a receptor and blocks the action of an agonist (like serotonin) but does not alter the receptor's intrinsic, baseline activity.[7] In contrast, an inverse agonist not only blocks the agonist but also reduces the receptor's constitutive activity—the signaling that occurs even in the absence of an agonist. This action effectively stabilizes the receptor in a fully inactive conformation.[7] While some debate exists whether the distinction between inverse agonism and simple antagonism is clinically significant for

5−HT2A​ receptors in the human brain, the functional outcome is a profound reduction in receptor-mediated signaling.[7]

The pathophysiological rationale for this mechanism is rooted in the neurobiology of Parkinson's disease. PDP is hypothesized to arise from an imbalance between the degenerating dopamine system and the serotonin system. As serotonin neurons also degenerate in Parkinson's disease, a compensatory upregulation of postsynaptic 5−HT2A​ receptors is thought to occur in cortical regions. Excessive stimulation of these hypersensitive receptors is believed to be a key driver of psychotic symptoms, especially the visual hallucinations that are a hallmark of PDP.[7] By potently blocking these overactive receptors, pimavanserin is thought to restore a more normal balance of serotonergic neurotransmission, thereby alleviating psychosis.[7]

Receptor Binding Profile and Selectivity

Pimavanserin's efficacy is coupled with a highly selective and "clean" receptor binding profile, which is the foundation of its favorable safety and tolerability. Quantitative binding assays reveal a precise targeting of the serotonin system with minimal off-target activity. This profile directly predicts its lack of common antipsychotic side effects, such as sedation (mediated by histamine H1​ receptors), orthostatic hypotension (mediated by α1​-adrenergic receptors), and anticholinergic effects like dry mouth and constipation (mediated by muscarinic receptors), making it particularly well-suited for the frail elderly population.[1] The binding affinities are summarized in Table 2.

Table 2: Receptor Binding Affinities (Ki​ values) of Pimavanserin

Receptor Target	Binding Affinity (Ki​ value)	Source(s)
Serotonin 5−HT2A​	0.087 nM	1
Serotonin 5−HT2C​	0.44 nM	1
Sigma-1	120 nM	1
Dopaminergic (D2​), Muscarinic, Histaminergic, Adrenergic	>300 nM (no appreciable affinity)	1

Pimavanserin demonstrates exceptionally high affinity for its primary target, the 5−HT2A​ receptor. Its affinity for the 5−HT2C​ receptor is approximately 40-fold lower, though engagement of this secondary target at therapeutic doses may contribute to its overall efficacy.[1] Crucially, it has no clinically relevant affinity for a wide range of other receptors typically implicated in the side effects of other antipsychotics.[1] This high degree of selectivity is what allows it to treat psychosis without inducing extrapyramidal symptoms or worsening motor function.[5]

Pharmacodynamics and Electrophysiological Effects

The selective receptor binding profile of pimavanserin translates into specific functional effects observed in preclinical and clinical studies. In animal models, pimavanserin effectively reduces behaviors induced by 5−HT2A​ receptor agonists, providing in vivo confirmation of its mechanism.[8] Furthermore, preclinical studies have shown that pimavanserin can act synergistically with traditional antipsychotics like haloperidol and risperidone to suppress hyperactivity, while at the same time attenuating the catalepsy (a proxy for extrapyramidal symptoms) induced by these drugs. This provided early, compelling evidence for its motor-sparing properties.[8]

A critical pharmacodynamic effect identified in clinical studies is a concentration-dependent prolongation of the QT interval on an electrocardiogram (ECG).[1] In clinical trials, mean increases of approximately 5-8 milliseconds were observed at the recommended therapeutic dose.[18] This effect is a key consideration for its cardiovascular safety profile and informs contraindications and warnings regarding its use in patients with pre-existing cardiac conditions or those taking other QT-prolonging medications.

Pharmacokinetics

The pharmacokinetic profile of pimavanserin is characterized by slow absorption, extensive distribution, metabolism via the cytochrome P450 system to a major active metabolite, and a long elimination half-life for both the parent drug and its metabolite.[17]

Absorption

Following oral administration, pimavanserin is absorbed with a median time to reach maximum plasma concentration (Tmax​) of 6 hours (range: 4-24 hours).[17] The presence of food has no clinically significant effect on its absorption; a high-fat meal resulted in a minor decrease in peak concentration (

Cmax​) of about 9% and a minor increase in total exposure (AUC) of about 8%, allowing the drug to be taken with or without food.[17] Pimavanserin exhibits dose-proportional pharmacokinetics over a wide range of single oral doses.[19]

Distribution

Pimavanserin is highly bound to human plasma proteins (approximately 95%) and has a large volume of distribution (Vd​) of 2,173 L, indicating extensive distribution into tissues.[10] It is not known if pimavanserin is distributed into human milk.[19]

Metabolism

Pimavanserin is extensively metabolized in the liver, primarily by cytochrome P450 enzymes CYP3A4 and CYP3A5, with minor contributions from other enzymes like CYP2J2 and CYP2D6.[17] The major metabolic pathway leads to the formation of an active N-desmethylated metabolite, known as AC-279.[17] This metabolite also reaches its peak concentration at a median

Tmax​ of 6 hours.[17] Importantly, pimavanserin and its active metabolite do not cause clinically significant induction or inhibition of major CYP enzymes, reducing the potential for certain types of drug-drug interactions.[17]

Excretion

Elimination of pimavanserin occurs primarily through metabolism, with very little of the unchanged drug excreted. After 10 days, only about 0.55% of an administered dose is recovered as unchanged drug in the urine and 1.53% in the feces.[17] The terminal elimination half-life (

t1/2​) of pimavanserin is approximately 57 hours. Its major active metabolite, AC-279, has a significantly longer half-life of approximately 200 hours.[17] These long half-lives contribute to the drug's suitability for once-daily dosing and mean that it takes several days to reach steady-state concentrations and a longer period to be fully cleared from the body after discontinuation.

Clinical Application and Investigational Uses

Approved Indication: Parkinson's Disease Psychosis

Pimavanserin is the first and only medication approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis.[3] This indication addresses the approximately 50% of individuals with Parkinson's disease who experience these symptoms over the course of their illness.[3] Clinical studies have demonstrated that pimavanserin significantly improves the frequency and severity of psychotic symptoms compared to placebo without worsening the core motor functions of Parkinson's disease, a key advantage over other antipsychotics.[3] In pivotal trials, 80.5% of individuals treated with pimavanserin reported an improvement in their symptoms.[1]

Dosage and Administration

The recommended dose of pimavanserin is 34 mg, administered orally once daily, without the need for dose titration.[2] It is available as capsules and tablets and can be taken with or without food.[6] For patients with dysphagia, the capsule may be opened and its contents sprinkled on soft food like applesauce or yogurt for immediate consumption.[17]

Dosage adjustments are required in specific clinical scenarios:

• Coadministration with Strong CYP3A4 Inhibitors: When used with strong inhibitors of the CYP3A4 enzyme (e.g., ketoconazole, clarithromycin), the dose of pimavanserin should be reduced to 10 mg once daily due to a significant increase in drug exposure.[13]
• Coadministration with Strong or Moderate CYP3A4 Inducers: Concomitant use with strong or moderate inducers of CYP3A4 (e.g., carbamazepine, rifampin, St. John's wort) should be avoided, as they can substantially decrease pimavanserin exposure and potentially reduce its efficacy.[13]
• Renal Impairment: No dose adjustment is needed for patients with mild to moderate renal impairment. However, due to increased drug exposure in patients with severe renal impairment (CrCl <30 mL/min), it should be used with caution in this population.[6]
• Hepatic Impairment: The use of pimavanserin is not recommended in patients with hepatic impairment, as its pharmacokinetics have not been studied in this population.[18]

Investigational and Off-Label Uses

Given its unique mechanism of action and favorable motor profile, pimavanserin is being actively investigated for other neuropsychiatric conditions.

• Dementia-Related Psychosis (DRP): Pimavanserin has been extensively studied for the treatment of hallucinations and delusions across various forms of dementia, including Alzheimer's disease, dementia with Lewy bodies, and vascular dementia.[6] It received an FDA Breakthrough Therapy Designation for this indication.[5] Although a supplemental New Drug Application (sNDA) for DRP was not approved by the FDA in 2021, clinical development continues, with Phase 3 trials like the HARMONY study evaluating its ability to prevent relapse of psychotic symptoms.[4]
• Other Psychiatric Disorders: There is emerging research into the potential use of pimavanserin as an adjunctive treatment for Major Depressive Disorder (MDD) in patients who have not responded adequately to SSRIs or SNRIs.[6] It is also being explored for treating refractory psychosis and negative symptoms in patients with schizophrenia and schizoaffective disorder, with Phase 3 trials underway as of March 2022.[5]

Safety Profile and Tolerability

Black Box Warning

Like all atypical antipsychotics, pimavanserin carries an FDA-mandated Black Box Warning regarding its use in a specific vulnerable population.

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. NUPLAZID is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson’s disease psychosis. 6

This warning highlights a class-wide effect observed with antipsychotic medications in this population and underscores that its safety and efficacy have only been established for psychosis specifically related to Parkinson's disease.

Contraindications, Warnings, and Precautions

Pimavanserin is contraindicated in patients with a known history of hypersensitivity or allergic reaction to the drug or its components. Reported reactions include rash, hives, and angioedema (e.g., swelling of the tongue, lips, or face; throat tightness).[13]

The most significant warning relates to its cardiovascular effects:

• QT Interval Prolongation: Pimavanserin prolongs the QT interval of the heart's electrical cycle, which can increase the risk of serious cardiac arrhythmias like Torsades de Pointes and sudden death.[25] Consequently, its use should be avoided in patients with:
• A known history of QT prolongation or congenital long QT syndrome.[25]
• A history of cardiac arrhythmias.[2]
• Other conditions that increase arrhythmia risk, such as symptomatic bradycardia (slow heartbeat), hypokalemia (low potassium), or hypomagnesemia (low magnesium).[2]
• Concomitant use of other drugs known to prolong the QT interval is also to be avoided.[13]

Adverse Events

In clinical trials and postmarketing experience, pimavanserin has been generally well-tolerated.

• Common Adverse Events: The most frequently reported side effects (occurring in ≥2% of patients and more often than placebo) include peripheral edema (swelling in hands, legs, or feet), nausea, confusional state, constipation, and gait disturbance.[26]
• Serious Adverse Events: Patients should be monitored for signs of QT prolongation, such as dizziness, feeling faint, or fast or pounding heartbeats.[27] Allergic reactions, as described under contraindications, require immediate medical attention. Postmarketing reports have also included agitation, aggression, and falls.[17]

Overdose Management

There is limited experience with pimavanserin overdose. In healthy subject studies, high doses were associated with nausea and vomiting.[1] There is no specific antidote for pimavanserin overdose. Management should be supportive, including immediate cardiovascular monitoring with continuous ECG recommended to detect potential QT prolongation.[1] If antiarrhythmic drugs are required, agents that themselves can prolong the QT interval (e.g., disopyramide, procainamide, quinidine) should not be used.[1]

Regulatory and Development History

The development of pimavanserin by ACADIA Pharmaceuticals was a targeted effort that began in the late 1990s, stemming from the observation that atypical antipsychotics with strong 5−HT2A​ receptor activity, like clozapine, were effective in PDP.[11] This led to a high-throughput screening campaign to identify a highly selective

5−HT2A​ inverse agonist, culminating in the discovery of pimavanserin (then known as ACP-103).[11]

Pimavanserin's path to market was marked by several key regulatory milestones with the U.S. FDA, highlighting its recognition as a significant therapeutic advance [20]:

• September 3, 2015: ACADIA Pharmaceuticals submitted the New Drug Application (NDA) for NUPLAZID for the treatment of Parkinson's disease psychosis.[31]
• November 2, 2015: The FDA granted Priority Review status to the NDA, a designation reserved for drugs that may offer significant improvements in treatment where no adequate therapy exists.[31]
• March 29, 2016: The FDA's Psychopharmacologic Drugs Advisory Committee voted 12 to 2 that the benefits of pimavanserin outweighed its risks for the proposed indication.[31]
• April 29, 2016: The FDA officially approved NUPLAZID (pimavanserin), making it the first and only drug approved to treat hallucinations and delusions associated with Parkinson's disease psychosis.[5] The approval was based primarily on the results of a single, pivotal 6-week, randomized, placebo-controlled Phase 3 trial.[5]
• June 29, 2018: The FDA approved a new 34 mg capsule formulation, simplifying the previous regimen of two 17 mg tablets.[31]
• September 20, 2018: Following a post-marketing safety review, the FDA issued a statement reaffirming the positive benefit-risk profile of NUPLAZID for its approved indication.[31]

Comparative Analysis and Place in Therapy

Pimavanserin in Context: A Comparison with Quetiapine and Clozapine

Prior to the approval of pimavanserin, clinicians managed PDP with the off-label use of other atypical antipsychotics, primarily quetiapine and clozapine, as they were considered less likely to worsen motor symptoms than older agents.[33] A comparison of these three agents reveals distinct profiles in mechanism, efficacy, and safety, which defines their respective places in therapy. This comparison is summarized in Table 3.

Table 3: Comparative Profile of Antipsychotics for Parkinson's Disease Psychosis

Feature	Pimavanserin	Clozapine	Quetiapine
Primary Mechanism	Selective 5−HT2A​ inverse agonist/antagonist. No D2​ activity.	Multi-receptor antagonist (D4​, 5−HT2A​, others); weak D2​ activity.	Multi-receptor antagonist (D2​, 5−HT2A​, others).
FDA Approval for PDP	Yes (U.S.) 6	No (U.S.); Yes (E.U.) 36	No (Off-label use) 36
Relative Efficacy	High 38	High (Potentially highest) 36	Low / Inconsistent 34
Key Motor Effects	Does not impair motor function 6	Does not impair motor function 38	Does not impair motor function 38
Key Cognitive Effects	No negative impact 43	Avoids cognitive impairment 39	Associated with significant cognitive decline 38
Major Safety Concern	QT Interval Prolongation 25	Agranulocytosis (requires blood monitoring) 45	Sedation, Cognitive Impairment, Mortality Risk 36

The choice of agent for PDP involves a critical trade-off between efficacy and distinct, non-overlapping safety risks. The decision between pimavanserin and clozapine, the two most effective agents, is often a choice between managing cardiovascular risk (QT prolongation with pimavanserin) versus managing hematological risk and logistical burden (agranulocytosis and blood monitoring with clozapine).[36] A patient's comorbidities, ability to adhere to monitoring, and overall clinical status are paramount in this decision. For instance, a patient with a history of cardiac arrhythmia would be a poor candidate for pimavanserin, while a patient living in a remote area or with poor compliance would be a poor candidate for clozapine. This context shows that the data does not suggest a simple hierarchy but rather defines distinct risk-benefit profiles that must be matched to the individual patient.

Synthesis of Evidence from Network Meta-Analyses

Multiple systematic reviews and network meta-analyses have sought to compare the available treatments for PDP. These studies provide quantitative estimates of relative efficacy and safety.

• Efficacy: A consistent finding is that pimavanserin and clozapine demonstrate significant efficacy in improving psychosis symptoms compared to placebo, whereas the evidence for quetiapine is weak or non-significant.[38] One analysis reported standardized mean differences (SMDs) for improvement on the Clinical Global Impression Scale for Severity (CGI-S) versus placebo as −4.81 for pimavanserin and −4.25 for clozapine, both highly significant.[38] Another analysis ranked clozapine first for psychotic symptom reduction (SMD −1.31) with pimavanserin second, while finding quetiapine to be significantly inferior to placebo (SMD +0.47).[41]
• Safety and Mortality: Retrospective analyses of large Medicare beneficiary databases have provided valuable real-world evidence. These studies suggest that patients with PD psychosis initiating pimavanserin have a lower risk of all-cause mortality compared to those initiating other off-label atypical antipsychotics.[43] One study found a 35% lower mortality risk in the first 180 days of treatment.[47] While this observational data cannot establish causality, it provides a strong signal supporting pimavanserin's relative safety in this vulnerable population.
• Acceptability: In terms of treatment continuation, one meta-analysis found that clozapine had the lowest all-cause dropout rates, suggesting high acceptability among patients who can tolerate it, despite having more dropouts specifically due to side effects.[38]

Defining the Therapeutic Niche and Patient Selection Criteria

Based on the totality of evidence, the therapeutic niches for each agent can be defined:

• Pimavanserin: Positioned as a first-line agent for PDP. Its specific FDA approval, robust efficacy data, favorable motor and cognitive safety profile, and supportive real-world mortality data provide a strong evidence-based rationale for its use.[6] It is an ideal choice for patients where dopaminergic blockade must be avoided and for those sensitive to sedation or cognitive side effects. The primary limitations are its potential for QT prolongation, which requires careful patient selection, and its high cost.[25]
• Clozapine: A highly effective, evidence-based option, potentially the most efficacious agent for treatment-refractory PDP.[38] Its use is reserved as a second-line or specialist choice due to the significant risk of agranulocytosis, which mandates a strict and burdensome hematological monitoring protocol.[45]
• Quetiapine: Despite inconsistent efficacy data and concerns about cognitive impairment, its continued off-label use suggests a perceived role in milder cases of PDP or when the risks and costs of pimavanserin and clozapine are considered prohibitive.[38] However, current evidence suggests it should be avoided in patients with pre-existing cognitive deficits.[38]

Synthesis and Future Perspectives

Integrated Benefit-Risk Assessment

Pimavanserin has established itself as a cornerstone in the management of Parkinson's disease psychosis. Its integrated benefit-risk profile is favorable for its approved indication. The primary benefit is its proven ability to effectively treat hallucinations and delusions without compromising the already impaired motor system of patients with Parkinson's disease—a unique and clinically vital attribute. This is weighed against its principal risks: the potential for QT interval prolongation, which necessitates careful cardiovascular assessment, and the class-wide increased risk of mortality in elderly patients with dementia-related psychosis, as highlighted in its Black Box Warning. For appropriately selected patients with PDP who lack significant cardiovascular contraindications, pimavanserin offers a targeted, effective, and well-tolerated treatment that represents a major therapeutic advance.

Unresolved Questions and Future Research Directions

Despite its success, several key questions remain, defining the future research trajectory for pimavanserin.

• Dementia-Related Psychosis (DRP): The most critical future direction is its potential application in the broader population of patients with DRP. This places the drug in the unique and challenging position of seeking an indication for the very condition described in its Black Box Warning.[6] The development program, which included a Breakthrough Therapy Designation from the FDA and the large HARMONY trial, aims to demonstrate that pimavanserin is an exception to the class-wide risk, offering a safe and effective treatment for this major unmet need.[4] The success or failure of this effort will have profound implications for the treatment of psychosis in the elderly and the regulatory interpretation of class-wide warnings.
• Other CNS Disorders: Preliminary research is exploring pimavanserin's utility in other disorders where 5−HT2A​ receptor modulation may be beneficial, including as an adjunctive therapy for major depressive disorder and for the negative symptoms of schizophrenia.[6] These investigations could significantly broaden its therapeutic scope.
• Long-Term Outcomes: While initial open-label extension and retrospective studies provide reassuring data on long-term use, continued post-marketing surveillance and real-world evidence studies are needed to fully characterize its effectiveness and safety over many years.[45]
• Head-to-Head Trials: The current comparative evidence is largely derived from placebo-controlled trials and indirect comparisons via network meta-analyses. There remains a significant need for well-designed, randomized, head-to-head clinical trials, particularly comparing pimavanserin directly with clozapine, to definitively establish their relative efficacy, safety, and place in therapy for Parkinson's disease psychosis.[33]

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