Classification of Antipsychotic Medications
Antipsychotics are traditionally classified into first-generation (typical), second-generation (atypical), and third-generation agents, though this classification system is increasingly recognized as clinically misleading and should not guide treatment selection. 1
Traditional Classification System
First-Generation (Typical) Antipsychotics
These agents function primarily as CNS dopamine receptor antagonists and are further subdivided by potency 1:
High-potency agents (e.g., haloperidol, droperidol, fluphenazine, perphenazine, pimozide, zuclopenthixol, trifluoperazine) are less sedating but cause more extrapyramidal symptoms 1
Low-potency agents (e.g., chlorpromazine, thioridazine) are more sedating with fewer extrapyramidal symptoms but greater anticholinergic, antihistaminic, and alpha-adrenergic effects 1, 2
Second-Generation (Atypical) Antipsychotics
These medications act as serotonin-dopamine receptor antagonists, offering different side effect profiles 1:
Examples include: amisulpride, asenapine, blonanserin, clozapine, levosulpiride, lurasidone, olanzapine, risperidone, paliperidone, quetiapine, ziprasidone 1, 3
Key distinction: Lower rates of extrapyramidal side effects and tardive dyskinesia compared to first-generation agents 4
Third-Generation Antipsychotics
These agents have partial dopamine receptor agonist activity, distinguishing them pharmacologically 1:
Examples include: aripiprazole, cariprazine, brexpiprazole, lumateperone 1
Mechanism: Aripiprazole is considered the first third-generation antipsychotic due to its partial D2 receptor agonist activity rather than pure antagonism 1
Critical Clinical Perspective
The distinction between first-generation and second-generation antipsychotics is not a distinct category from either a pharmacological or clinical perspective and should not be used to guide psychotropic choice. 1 This represents the most current expert consensus from international guidelines.
Why This Classification Is Problematic
Both typical and atypical antipsychotics carry similarly increased risks of sudden cardiac death, with dose-dependent effects (adjusted incidence-rate ratios from 1.31 to 2.42 for typical agents and 1.59 to 2.86 for atypical agents) 1
The heterogeneity within each class is substantial—second-generation antipsychotics vary dramatically in their effectiveness and side effect profiles 5
Treatment selection should be based on individual drug pharmacodynamic profiles, side-effect profiles, and patient-specific factors rather than generational classification 1
Practical Clinical Approach
When selecting antipsychotics, switch to compounds with different pharmacodynamic profiles rather than relying on generational categories. 1 For example, if a patient fails a D2 partial agonist (third-generation), consider switching to amisulpride, risperidone, paliperidone, or olanzapine (second-generation agents with different receptor profiles) 1.
Common Pitfalls to Avoid
Do not assume atypical antipsychotics are universally safer—both classes carry cardiac risks and require monitoring 1
Recognize metabolic heterogeneity—some second-generation agents (particularly olanzapine and clozapine) carry substantial metabolic burden, while others have minimal effects 5, 4
Clozapine remains unique among all antipsychotics for treatment-resistant schizophrenia, suicide reduction, and improved longevity, regardless of its classification as "second-generation" 4