Second-generation antipsychotics — SGAs, the "atypicals" — were developed to retain the antipsychotic effect of FGAs while reducing the EPS burden that limited their use. The defining feature is the addition of 5-HT2A antagonism to D2 antagonism. The combination, in theory, modulates how D2 blockade affects different pathways differently — particularly reducing nigrostriatal EPS while preserving mesolimbic antipsychotic effect.
- Class
- Second-Generation (Atypical) Antipsychotics
- Mechanism
- D2 antagonism + 5-HT2A antagonism (the defining "atypical" feature). The 5-HT2A blockade in cortex and nigrostriatal pathways reduces EPS and may improve negative/cognitive symptoms.
- Typical dose
- Drug-specific
- Half-life
- Drug-specific
- FDA indications
- Schizophrenia, bipolar disorder, MDD augmentation (some agents), irritability in autism (specific agents)
- Key adverse effects
- Metabolic syndrome (weight gain, lipids, glucose — varies widely by agent), sedation, EPS (less than FGAs but present), hyperprolactinemia (risperidone/paliperidone prominent), QTc prolongation (ziprasidone)
- Representative agents
- Risperidone, paliperidone, olanzapine, quetiapine, ziprasidone, lurasidone, asenapine, iloperidone, lumateperone, clozapine
Black box: Increased mortality in elderly patients with dementia-related psychosis
The "atypical" label refers to lower EPS at therapeutic doses than FGAs — the 5-HT2A antagonism is hypothesized to mediate this. Metabolic burden replaces EPS as the central tolerability concern. Wide variation within the class — selection by patient-specific factors.
The trade-off changed but didn't disappear. EPS is reduced. Metabolic burden — weight gain, lipid dysregulation, glucose intolerance, sometimes new-onset diabetes — is added. The signature of SGAs is that metabolic syndrome replaces EPS as the central long-term tolerability concern.
Second-generation antipsychotics modify the FGA mechanism by adding 5-HT2A antagonism (or, in third-generation agents, D2 partial agonism) — changing the EPS and negative-symptom profile while introducing a metabolic liability.
Mechanism note: The SGA bargain: 5-HT2A antagonism (or D2 partial agonism) buys lower EPS and prolactin at the cost of metabolic risk. Agent selection is largely a metabolic-profile decision.
Within-class differences are substantial. Olanzapine and clozapine carry the highest metabolic burden. Quetiapine is intermediate. Risperidone and paliperidone have moderate metabolic effect with high prolactin elevation. Aripiprazole, lurasidone, ziprasidone, cariprazine, and lumateperone have the lowest metabolic burden. Within EPS: risperidone has the most among SGAs (dose-dependent above 6 mg), while clozapine and quetiapine have the least.
These differences matter for patient-specific selection. The patient with obesity, prediabetes, or family history of metabolic syndrome should rarely start olanzapine first; aripiprazole or lurasidone is often better. The patient with prior EPS history should avoid risperidone above 4 mg. The patient with QTc concerns should avoid ziprasidone. The patient with severe negative symptoms might benefit from cariprazine's D3 preference. Match drug to patient, not class to diagnosis.
Monitoring is consistent across the class: weight every visit, blood pressure quarterly, fasting glucose and A1c annually (sooner if weight rising), lipid panel annually, AIMS exam annually, prolactin if symptomatic. The framework is the same; the agent-specific concerns vary.
SGAs are first-line for schizophrenia in most modern practice. The choice within the class is where the clinical thinking lives.