Pimavanserin
Nuplazid
Selective Serotonin Inverse Agonist (Atypical Antipsychotic)
Pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT2A receptors (Ki 0.087 nM) and to a lesser extent at 5-HT2C receptors (Ki 0.44 nM). It has no appreciable affinity (Ki >300 nM) for dopaminergic (including D2), muscarinic, histaminergic, or adrenergic receptors. This non-dopaminergic mechanism eliminates the risk of worsening Parkinsonian motor symptoms, EPS, and tardive dyskinesia — making it uniquely suited for Parkinson's disease psychosis where dopamine blockade is contraindicated.
Compare Pimavanserin →FDA-Approved Indications
- Hallucinations and delusions associated with Parkinson's disease psychosis
Common Off-Label Uses
- Hallucinations and delusions in Lewy body dementia (theoretical; mechanism-based)
- Hallucinations in dementia of all causes (Phase 3 data; FDA rejected broader indication)
- Negative symptoms of schizophrenia adjunct (augmenting atypical antipsychotics; in trials)
- Treatment-resistant depression adjunct (augmenting antidepressants; in trials)
What Sets This Drug Apart
- ONLY antipsychotic FDA-approved specifically for Parkinson's disease psychosis (hallucinations and delusions)
- Zero dopamine receptor affinity (Ki >300 nM for D2) — cannot worsen Parkinsonian motor symptoms, no EPS, no tardive dyskinesia risk
- Highest 5-HT2A binding affinity of any antipsychotic (Ki 0.087 nM) with selective inverse agonist mechanism
- No metabolic burden — no affinity for muscarinic or histaminergic receptors. Weight neutral.
- Very long half-life (57h parent, 200h active metabolite) — takes ~2 weeks to reach steady state and ~2 weeks to wash out
- QT prolongation concern — 5-8 msec at therapeutic dose, contraindicated with other QT-prolonging drugs
Boxed Warning
Increased mortality in elderly patients with dementia-related psychosis