Second-Generation Antipsychotics for Psychosis
Second-generation antipsychotics (SGAs) include amisulpride, asenapine, blonanserin, clozapine, levosulpiride, lurasidone, olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, sertindole, iloperidone, and zotepine. 1
Complete List of Second-Generation Antipsychotics
The following medications are classified as second-generation (atypical) antipsychotics used for treating psychosis:
Core Second-Generation Agents
- Amisulpride - a serotonin-dopamine receptor antagonist with established efficacy in schizophrenia 1, 2
- Asenapine - available in transdermal formulation with lower metabolic liability 2, 3
- Blonanserin - included in systematic reviews of antipsychotic treatments 1
- Clozapine - the gold standard for treatment-resistant schizophrenia, requiring plasma levels of 350-420 ng/ml for optimal response 1, 2
- Iloperidone - a newer SGA with lower propensity for weight gain 2, 3
- Levosulpiride - recognized in international treatment guidelines 1
- Lurasidone - demonstrates the best profile for minimizing weight gain and metabolic abnormalities among SGAs 2, 3
- Olanzapine - effective but associated with significant metabolic side effects; therapeutic range 20-50 ng/ml 1, 2
- Paliperidone - the active metabolite of risperidone, available in extended-release formulation 4, 2
- Quetiapine - a serotonin-dopamine antagonist with sedating properties 2, 5
- Risperidone - first-line option with established efficacy; recommended initial dose 2 mg/day in first-episode psychosis 1, 2
- Sertindole - included in comprehensive safety reviews of SGAs 5, 6
- Ziprasidone - lower metabolic liability but requires administration with food for adequate absorption 7, 2
- Zotepine - included in dose equivalence studies 6
Important Clinical Distinction
The classification of antipsychotics into "first-generation" versus "second-generation" is not a distinct category from either a pharmacological or clinical perspective and should not be used to guide medication choice. 8, 9
- Treatment selection should be based on individual drug pharmacodynamic profiles, side-effect profiles, and patient-specific factors rather than generational classification 9
- Both typical and atypical antipsychotics carry similarly increased risks of sudden cardiac death with dose-dependent effects 9
Third-Generation Antipsychotics (Partial Dopamine Agonists)
While technically distinct from SGAs, the following are sometimes grouped with second-generation agents:
- Aripiprazole - partial D2 agonist with lower metabolic risk 1, 9
- Brexpiprazole - newer partial agonist with improved tolerability 1, 3
- Cariprazine - partial agonist with efficacy for negative symptoms 1, 3
- Lumateperone - novel mechanism targeting serotonin, dopamine, and glutamate systems 1, 3
Critical Prescribing Considerations
- When switching antipsychotics due to inadequate response, select agents with different pharmacodynamic profiles rather than simply choosing another "second-generation" drug 8, 10
- For patients failing a D2 partial agonist, consider amisulpride, risperidone, paliperidone, or olanzapine (with samidorphan or concurrent metformin) 8
- Clozapine remains the only antipsychotic with proven superiority for treatment-resistant psychosis and should be initiated after two adequate trials of other antipsychotics fail 8, 10