Treatment of Parkinson's Disease Psychosis

Andrew Schleisman, PharmD Candidate 2017; Mikayla Spangler, PharmD, BCPS; Emily Knezevich, PharmD, BCPS, CDE


US Pharmacist. 2016;41(11):HS-20-HS-26. 

In This Article

Antipsychotic Treatment

Atypical Antipsychotics

The typical antipsychotics are widely known to exacerbate motor symptoms in PD patients and thus play virtually no role in the treatment of PDP, except in acute circumstances when neuropsychiatric control is necessary over motor control.[11,18] The underlying mechanism of motor-symptom exacerbation is likely related to high D2-receptor antagonism.[11] Although D2-receptor affinity crosses over to the atypical antipsychotics as well, in clinical studies two atypical antipsychotics (clozapine and quetiapine) with low D2-receptor affinity have demonstrated improved psychotic symptoms without dramatically worsened motor symptoms.[9,16] Other atypical antipsychotics are not considered for use in PDP because of their high likelihood of worsening motor symptoms. Other neurotransmitter systems linked to PDP, such as serotonin, are impacted by atypical antipsychotics and likely contribute to their efficacy in this population. See Table 2 for receptor-binding affinities of selected atypical antipsychotics.[19]


Clozapine was the first atypical antipsychotic approved for use in the United States.[20] Clozapine is indicated for schizophrenia and schizoaffective disorder, but in clinical trials it was shown to consistently improve symptoms of PDP without worsening motor control.[9,21–24] Clozapine is a dibenzothiazepine derivative classically described as a dopamine antagonist with a low affinity for D2 receptors and a higher affinity for D1, D3, D4, and 5-HT2A (serotonin) receptors.[20] Additionally, clozapine has rapid dissociation from the D2 receptor.[20] The combination of low D2-receptor affinity and high 5-HT2A receptor binding likely accounts for clozapine's effectiveness and absence of motor-function aggravation. Clozapine is also associated with adrenergic, cholinergic, and histaminergic antagonism, which probably explains its related adverse effects. Dosing in the setting of PDP is significantly lower than that typically used in the treatment of schizophrenia, which may additionally explain clozapine's lack of aggravation of motor symptoms. Dosages studied in clinical trials ranged from 6.25 mg to 50 mg, with mean dosages of 25 mg/day.[9,20,22–24] See Table 3 for a summary of clozapine in the treatment of PDP.

In 2006, the American Academy of Neurology (AAN) released guidelines stating that clozapine should be considered for PD patients with psychosis, but that the absolute neutrophil count (ANC) must be monitored.[14] The 2011 guidelines of the Movement Disorder Society (MDS) concluded that clozapine is efficacious, noting that it has an acceptable safety risk and requires specialized monitoring.[5] Monitoring includes frequent WBC count testing to assess for rare but potentially life-threatening agranulocytosis, which occurs in 0.38% of patients.[5] Because of this risk, clozapine has a Risk Evaluation and Mitigation Strategies program that recommends ANC monitoring weekly from drug initiation to 6 months, followed by biweekly monitoring from 6 to 12 months, and then monthly monitoring thereafter. More frequent monitoring is required if a patient develops neutropenia.[25] Most physicians and pharmacists have insufficient experience with clozapine because of the need for hematologic monitoring, which is a burden for patients and practitioners and results in the underuse of clozapine in the clinical setting.


This dibenzothiazepine derivative is indicated for schizophrenia, bipolar disorder, mania, and adjunctively for depression.[26] Quetiapine is associated with a relatively higher affinity for 5-HT2A receptors than for D2 receptors, which makes it another option for the treatment of PDP.[20] Its high affinity for adrenergic and histaminergic receptors explains common adverse events such as orthostatic hypotension and sedation.[20] In a recent systematic review of randomized, controlled trials involving quetiapine for PDP, mean daily dosages of quetiapine ranged from 58.3 mg to 169.1 mg.[27] The suggested initial dosage is 12.5 mg daily, and it may be titrated to a maintenance dose of up to 150 mg.[9] See Table 3 for a summary of quetiapine in the treatment of PDP. More reports of worsening PD symptoms have been associated with quetiapine than with clozapine. In the systematic review mentioned above, 10 of 122 patients receiving quetiapine experienced PD deterioration, but the total dropout rate of 32.4% may have led to underestimation of this effect.[27]

Based on inconsistent and conflicting efficacy results in open-label and randomized, controlled trials with both placebo and clozapine as comparators,[28] the MDS guidelines concluded that evidence was insufficient to recommend quetiapine for PDP.[5] Similar to clozapine, quetiapine was considered to have an acceptable safety risk; unlike clozapine, however, specialized monitoring is not required.[5] The AAN guidelines stated that quetiapine may be considered for PDP, based on a study demonstrating possible improvement of psychosis.[14] Although clinical studies have yet to definitively demonstrate its benefit, quetiapine is generally regarded as first-line therapy because of safety and monitoring concerns associated with clozapine.[29]


The 2006 AAN guidelines identified the need for evidence of efficacy of novel antipsychotics without dopamine antagonistic effects.[14] Pimavanserin acts as an inverse agonist on 5-HT2A receptors and has no significant effect on dopaminergic, muscarinic, histaminic, or adrenergic receptors.[29,30] Clinical studies have demonstrated both safety and efficacy without worsening of motor function. A 28-day randomized, placebo-controlled, double-blind, phase II trial with a 4-week follow-up period found no statistically significant difference in motor function based on the Unified Parkinson's Disease Rating Scale. Efficacy, as evaluated with the Scale for the Assessment of Positive Symptoms (SAPS), showed statistically significant improvement in the global rating of both hallucinations and delusions. Trends were seen in other areas of the SAPS. No significant differences with regard to adverse events were seen between the placebo and pimavanserin groups.[29]

A 6-week randomized, placebo-controlled, phase III trial of 199 patients had similar results, with no evidence of treatment-related impairment of motor function between the placebo and pimavanserin groups. The study reached its primary endpoint of antipsychotic benefit for pimavanserin compared with placebo, which was assessed by a PD-adapted SAPS (SAPS-PD). There was a comparative mean decrease of 3.06 on the SAPSPD scale for pimavanserin versus placebo (P = .001) and an overall decrease of 37% from baseline.[31] A validation study for the SAPS-PD scale found that a reduction of 2.33 is considered clinically significant based on a one-point improvement on the Clinical Global Impression–Improvement scale, a seven-point, clinician-driven assessment of a patient's overall mental illness.[32] These results demonstrate that pimavanserin may have significant benefit in clinical practice. Pimavanserin was generally well tolerated, although 10 pimavanserin-treated patients discontinued treatment because of an adverse event (four of which were due to psychosis) versus two discontinuations for adverse events in the placebo group.[31] A meta-analysis of four randomized, controlled trials of pimavanserin—including the two mentioned above and two unpublished studies—concluded that pimavanserin is beneficial for the treatment of PDP and has good tolerability.[9] Pimavanserin has not been studied in any head-to-head trials with clozapine or quetiapine.

Based on the promising results of the phase II and phase III trials, the FDA approved pimavanserin (Nuplazid) on April 29, 2016, as the first drug indicated to treat hallucinations and delusions associated with PDP.[33] Nuplazid, which is available as 17-mg tablets, has a recommended dosage of 34 mg taken orally once daily, with no titration needed; it may be taken with or without food. As with other antipsychotics, pimavanserin carries a black box warning regarding increased mortality in elderly patients with dementia-related psychosis. No study has directly linked pimavanserin to this risk, but the FDA considers the risk a class effect. Pimavanserin can cause QT interval prolongation and is metabolized by the CYP3A4 enzyme, so caution should be exercised. If a strong CYP3A4 inhibitor is used, the dosage should be reduced to 17 mg per day. Pimavanserin is not recommended in patients with hepatic impairment or severe renal impairment (creatinine clearance <30 mL/min).[34] See Table 3 for a summary of pimavanserin in the treatment of PDP.

The high cost of pimavanserin will likely limit prescribing, and as with many name-brand products currently on the market, the manufacturer is currently offering a program to assist patients with the insuranceapproval process.[35,36] Because of the safety, efficacy, and lack of motor worsening seen in clinical trials, pimavanserin shows promise; however, with no head-to-head trial data available, it is difficult to ascertain this agent's exact fit in current therapy.