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Atypical Antipsychotic — Selective 5-HT2A Inverse Agonist (Parkinson's Disease Psychosis) Pregnancy: Avoid — insufficient human data. Effective contraception required during treatment.

Pimavanserin

Brand names: Nuplazid

Adult dose

Dose: 34 mg once daily
Route: Oral
Frequency: Once daily
Max: 34 mg/day
Hallucinations and delusions associated with Parkinson's disease psychosis (PDP). MHRA conditional approval 2021 in the UK. Does NOT worsen Parkinson's motor symptoms — no dopamine D2 blockade. Can be taken with or without food. Source: BNF 90; MHRA SPC Nuplazid.

Paediatric dose

Dose: Not licensed under 18 years N/A/kg
Route: N/A
Frequency: N/A
Max: N/A
Not licensed for paediatric use.

Dose adjustments

Renal

No dose adjustment for mild-moderate renal impairment. Severe renal impairment (eGFR <30 mL/min): not recommended — limited data.

Hepatic

Moderate-severe hepatic impairment: not recommended — significantly increased pimavanserin AUC.

Paediatric weight-based calculator

Not licensed for paediatric use.

Clinical pearls

  • The Parkinson's psychosis treatment dilemma: conventional antipsychotics (haloperidol, risperidone) worsen motor symptoms in PD by blocking D2 receptors in the nigrostriatal pathway. Quetiapine and clozapine have been used off-label (quetiapine limited efficacy; clozapine requires weekly FBC monitoring). Pimavanserin's selective 5-HT2A inverse agonism treats psychosis WITHOUT D2 blockade — motor-sparing is the pivotal advantage.
  • ACP-103 (ACPNJ-103) mechanism: 5-HT2A receptors in the cortex and limbic system modulate dopamine function and perception. 5-HT2A inverse agonism reduces aberrant serotonin signalling that contributes to visual hallucinations in PD psychosis — without directly antagonising dopamine in the striatum.
  • HARMONY trial (Lancet 2021): pimavanserin significantly delayed time to relapse of psychosis in patients with PD dementia vs placebo (HR 0.353). First pivotal maintenance trial in PD psychosis confirming long-term benefit.
  • QTc monitoring critical: obtain ECG before starting (baseline QTc). If QTc >500 ms — do not start. If QTc increases >60 ms from baseline or exceeds 500 ms during treatment — reduce dose or stop. Especially important in PD patients who may also be on other QTc-prolonging drugs (amantadine, ondansetron for nausea, some antibiotics).
  • MHRA 2021 conditional approval: pimavanserin was approved in the UK with conditions — prescribing by neurologists or geriatricians with PD experience, QTc monitoring requirement. Not widely available in all NHS trusts — check local formulary. Source: BNF 90; Ballard et al. Lancet 2021 (HARMONY); MHRA SPC Nuplazid.

Contraindications

  • QTc >500 ms at baseline (QTc prolongation — MHRA warning)
  • Concomitant drugs that prolong QTc and are also strong CYP3A4 inhibitors (additive QTc risk)
  • Severe hepatic impairment
  • History of cardiac arrhythmia at risk for torsade de pointes

Side effects

  • QTc prolongation (most important — dose-dependent; MHRA warning; monitor ECG pre-treatment and periodically)
  • Peripheral oedema, nausea, confusion (most common adverse effects)
  • Falls (in already-vulnerable PD population)
  • Hallucinations (paradoxical worsening — rare)
  • No extrapyramidal side effects (no D2 blockade — key advantage in PD)

Interactions

  • Strong CYP3A4 inhibitors (clarithromycin, itraconazole, ketoconazole): increase pimavanserin exposure up to 3-fold — reduce dose to 10 mg once daily
  • Strong CYP3A4 inducers (rifampicin, carbamazepine): reduce pimavanserin levels — avoid
  • QTc-prolonging drugs (amiodarone, haloperidol, ondansetron, methadone, moxifloxacin): additive QTc prolongation — avoid combination or ECG monitor
  • Moderate CYP3A4 inhibitors (fluconazole, erythromycin, diltiazem): increase pimavanserin — reduce dose

Monitoring

  • ECG at baseline and after dose changes (QTc monitoring — monthly for 3 months, then every 6 months)
  • Neuropsychiatric symptoms (hallucinations, delusions — severity scoring with NPI or UPDRS Part I)
  • Parkinson's motor assessment (confirm no motor worsening — expected advantage of pimavanserin)
  • Peripheral oedema (weight, ankle swelling)
  • Cognitive function (PD dementia progression)

Reference: BNFc; BNF 90; Ballard et al. Lancet 2021 (HARMONY trial); MHRA SPC Nuplazid; Cummings et al. Lancet 2014 (Phase III PDP trial). Verify against your local formulary and the latest BNF before prescribing.

Related

Curated clinical cross-links plus same-class fallbacks.

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