Pharmacology  ·  Antipsychotic Drugs

Second-Generation Antipsychotics: Core Agents

Clozapine, olanzapine, quetiapine, risperidone, and paliperidone — receptor profiles and clinical trade-offs

• Second-generation antipsychotics are often described as a class, but they are not pharmacologically uniform. The comparison table shows that each agent has a distinct receptor binding profile, and those differences predict which adverse effects dominate — not which antipsychotic effect one gets, since antipsychotic efficacy is broadly equivalent across all of them except for clozapine.
• The three color-coded risk columns — extrapyramidal, metabolic, prolactin — almost never peak together in the same agent. Clozapine has the worst metabolic profile and the best motor profile. Risperidone has the worst prolactin profile. Quetiapine has the best combined motor and prolactin profile, at the cost of moderate metabolic risk. These trade-offs, not differences in antipsychotic efficacy, drive agent selection.
• Clozapine is separated into its own section because it occupies a different clinical space from the rest of the table. It is not simply another second-generation agent with a different profile — it is the only drug that works when nothing else does, and it carries the only Food and Drug Administration indication for reducing suicidal behavior in schizophrenia. The reason it is underused is in the adverse effect card.
• Agranulocytosis is what drives clozapine's mandatory monitoring program. The absolute neutrophil count requirement is not flexible, and the monitoring schedule — weekly for six months, then biweekly, then monthly — is the price of using the drug. Myocarditis in the first eight weeks is the other time-sensitive hazard that requires active surveillance.
• The drug interaction rule box closes the section because cytochrome P450 interactions are clinically consequential for three of these five agents. Smoking status affects clozapine and olanzapine levels enough to require dose adjustment on initiation or cessation, and the quetiapine-carbamazepine interaction can reduce levels to subtherapeutic concentrations.