Chapter 16  ·  Module 4  ·  Introduction to Medical Pharmacology

Newer Second-Generation Antipsychotics

Partial agonists, metabolically favorable full antagonists, and their distinguishing clinical profiles

Agent Comparison — Receptor Profile and Key Clinical Properties

Agent Mechanism Extrapyramidal Symptom Risk Akathisia Risk Metabolic Risk Prolactin Key Distinguishing Feature
Partial D2 Agonists
Aripiprazole Partial D2 + 5-HT1A agonist; 5-HT2A antagonist Very low Moderate–High Very low None Broadest indication range; longest half-life (75 hr); dual CYP2D6/3A4 metabolism
Brexpiprazole Partial D2/D3 agonist; lower intrinsic efficacy than aripiprazole Very low Low–Moderate Very low None Lower akathisia than aripiprazole; more alpha-1 blockade (orthostatic hypotension)
Cariprazine D3-preferential partial agonist (D3:D2 ratio 10:1) Very low High at doses above 4.5 mg Very low None Best evidence for negative symptoms; active metabolite persists weeks after stopping
Full D2 Antagonists — Metabolically Favorable
Ziprasidone D2 + 5-HT2A antagonist; low H1/M1 Low Low Very low Minimal QTc prolongation — baseline electrocardiogram required; must take with food (500 cal)
Lurasidone D2 + 5-HT2A + 5-HT7 antagonist; low H1/M1 Low Low Very low Minimal Best evidence for bipolar depression; CYP3A4 only — strong inhibitors/inducers contraindicated; must take with food (350 cal)
Full D2 Antagonists — Niche Agents
Asenapine Broad receptor profile; D2 + multiple serotonin subtypes + H1 Low Low Moderate Minimal Sublingual only — zero oral bioavailability; no food/drink 10 min after dosing
Iloperidone D2 + 5-HT2A + strong alpha-1 blockade Low Low Moderate Minimal Mandatory 7-day titration (alpha-1 hypotension); QTc prolongation; schizophrenia only

Special Considerations

Food Dependency — Ziprasidone and Lurasidone

  • Ziprasidone: Take with at least 500 calories — bioavailability doubles with food vs. fasting
  • Lurasidone: Take with at least 350 calories — bioavailability triples with food vs. fasting
  • Without food: plasma levels may be insufficient for antipsychotic effect
  • This is a pharmacokinetic requirement — not a dietary suggestion
  • If patient appears to have reduced response: reassess food adherence before increasing dose

QTc and Cardiac Considerations

  • Ziprasidone: Mean QTc prolongation approximately 10 ms — baseline electrocardiogram required
  • Iloperidone: Modest QTc prolongation — baseline electrocardiogram required
  • Both contraindicated with known QTc prolongation or congenital long QT syndrome
  • Additive QTc risk with fluoroquinolones, azole antifungals, macrolides, antiarrhythmics, methadone
  • Partial agonists (aripiprazole, brexpiprazole, cariprazine): negligible QTc effect

Cariprazine negative symptom evidence: The only antipsychotic with a prospective randomized trial powered specifically for a primary negative symptom endpoint — demonstrated superiority over risperidone in patients with predominant negative symptoms over 26 weeks (Nemeth et al., Lancet, 2017). Active metabolite persists 1–3 weeks after stopping — adverse effects resolve slowly.

Drug interaction rules for partial agonists: Aripiprazole and brexpiprazole — CYP2D6 or CYP3A4 inhibitor alone: reduce dose 50%. Both inhibited simultaneously: reduce dose to 25%. CYP3A4 inducer: double dose. Cariprazine — CYP3A4 inhibitor: halve dose. CYP3A4 inducer: avoid. Lurasidone — strong CYP3A4 inhibitors and inducers: contraindicated.