Pharmacology · Antipsychotic Drugs

Newer Second-Generation Antipsychotics

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

The agents in this module split into a mechanistically distinct group and a pragmatically defined group. The partial D2 agonists — aripiprazole, brexpiprazole, cariprazine — differ from all earlier antipsychotics in kind, not degree: they reduce dopamine tone in the mesolimbic pathway without abolishing it, which is why they have near-zero metabolic risk and no prolactin elevation. The full antagonists in the lower rows are here because they share the same favorable metabolic profile, not because they share the same mechanism.
The akathisia column is where the partial agonist advantage partially reverses. Aripiprazole and cariprazine have meaningfully higher akathisia rates than olanzapine or quetiapine, and cariprazine's akathisia risk at doses above 4.5 mg is the main dose-limiting factor. Brexpiprazole was designed to reduce this by lowering intrinsic efficacy at the D2 receptor, at the cost of more alpha-1 blockade.
Cariprazine's D3 preference is what separates it from aripiprazole beyond the akathisia difference. D3 receptors are concentrated in prefrontal and limbic areas involved in motivation and cognition rather than the ventral striatum. The Lancet randomized trial powered specifically for negative symptoms is the strongest evidence to date that targeting D3 preferentially matters clinically.
Ziprasidone and lurasidone are metabolically favorable full antagonists whose clinical uptake has been limited by the food requirement and, for ziprasidone, the QTc concern. The food dependency is pharmacokinetic, not optional — absorption triples or doubles with a meal, and a patient who appears to be a treatment non-responder may simply be taking the drug on an empty stomach.
The drug interaction rule box is dense but clinically critical for these agents because the cytochrome P450 relationships determine the dose adjustments needed whenever inhibitors or inducers are co-prescribed. Lurasidone's contraindication with strong CYP3A4 inhibitors and inducers is absolute, not a soft caution.

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.

Suggested References

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