Iloperidone
Fanapt
Second-Generation Antipsychotic (SGA)Generic availableTDM data
Iloperidone acts as an antagonist at D2 (Ki 6.3 nM), 5-HT2A (Ki 5.6 nM), and D3 (Ki 7.1 nM) receptors, with very potent alpha-1 adrenergic antagonism (Ki 0.36 nM). Alpha-1 blockade (Ki 0.36 nM) is iloperidone's highest-affinity binding per FDA label Section 12.2, and drives orthostatic hypotension, necessitating mandatory slow titration. No appreciable muscarinic affinity (Ki >1000 nM), eliminating anticholinergic burden. Active metabolite P88 has similar receptor profile; metabolite P95 is selective for 5-HT2A and adrenergic receptors.
Compare Iloperidone →FDA-Approved Indications
- Schizophrenia in adults
- Acute bipolar I mania/mixed episodes in adults
Common Off-Label Uses
- Psychosis refractory to other antipsychotics
- PTSD-related nightmares (theoretical — potent alpha-1 blockade, analogous to prazosin mechanism)
- Bipolar depression (not FDA-approved but studied)
What Sets This Drug Apart
- Most potent alpha-1 adrenergic antagonist among SGAs (Ki 0.36 nM) — drives mandatory titration and orthostatic hypotension but also explains low EPS via downstream mechanisms
- CYP2D6-dependent metabolism with pharmacogenomic implications — 7-10% of Caucasians are PMs requiring half dose; QTc prolongation doubles (9→19 msec) with metabolic inhibition
- Zero anticholinergic burden (M1 Ki >1000 nM) — no dry mouth, constipation, or cognitive effects from muscarinic blockade
- Dual indication: schizophrenia AND acute bipolar I mania/mixed episodes
- Significant hepatic transaminase elevations in bipolar mania trial — ALT ≥3x ULN in 9.2% vs 1.5% placebo
- Priapism and intraoperative floppy iris syndrome (IFIS) from alpha-1 blockade — unique among SGAs in frequency of these reports
Boxed Warning
Increased mortality in elderly patients with dementia-related psychosis — not approved for this use