First-generation antipsychotics — FGAs, the "typicals" — were the breakthrough that defined the antipsychotic era. Chlorpromazine in 1952 transformed asylum psychiatry. Haloperidol followed and became the dominant agent for decades. The mechanism is essentially pure D2 antagonism, and the entire clinical profile flows from that single mechanistic fact applied across multiple dopamine pathways.
- Class
- First-Generation (Typical) Antipsychotics
- Mechanism
- Pure D2 receptor antagonism (high-potency) or D2 + multi-receptor activity (low-potency)
- Typical dose
- Drug-specific
- Half-life
- Drug-specific
- FDA indications
- Schizophrenia, schizoaffective disorder, acute mania, severe agitation, Tourette syndrome
- Key adverse effects
- Extrapyramidal symptoms (acute dystonia, akathisia, parkinsonism, tardive dyskinesia), hyperprolactinemia, neuroleptic malignant syndrome (NMS), QTc prolongation
- Representative agents
- High-potency: haloperidol, fluphenazine, thiothixene, trifluoperazine. Mid-potency: perphenazine, loxapine. Low-potency: chlorpromazine, thioridazine.
Black box: Increased mortality in elderly patients with dementia-related psychosis
Largely supplanted by SGAs as first-line due to EPS burden. Specific modern niches: rapid agitation control (IM haloperidol), Tourette syndrome, long-acting injectables for adherence, low-cost option in resource-limited settings.
The D2 receptor exists in at least four major dopaminergic pathways in the brain. The mesolimbic pathway carries dopamine that, when excessive, produces positive psychotic symptoms — blocking it there is the therapeutic effect. The nigrostriatal pathway carries dopamine that controls movement — blocking it there causes EPS. The tuberoinfundibular pathway carries dopamine that suppresses prolactin — blocking it there causes hyperprolactinemia. The mesocortical pathway carries dopamine to PFC and may already be hypoactive in schizophrenia — blocking it there may worsen negative and cognitive symptoms. One drug, four pathway effects.
First-generation antipsychotics share a single therapeutic mechanism — D2 blockade — and a single defining liability: that same blockade in the wrong pathway produces movement disorders.
Mechanism note: The FGA class is one mechanism (D2 blockade) producing four pathway-specific effects — one therapeutic, three problematic. Potency predicts the EPS/sedation trade-off across agents.
FGAs cannot distinguish between these pathways. The therapeutic mesolimbic blockade and the nigrostriatal EPS and the tuberoinfundibular prolactin elevation all happen at once. That's the inescapable trade-off of the class.
FGAs span a potency spectrum. High-potency agents — haloperidol, fluphenazine — are pure D2 with minimal off-target activity. More EPS, less sedation, less anticholinergic, less orthostasis. Low-potency agents — chlorpromazine — block D2 plus significant H1, M1, and alpha-1 receptors. Less EPS (because anticholinergic effect partially offsets the EPS), but more sedation, more orthostasis, more anticholinergic burden. Mid-potency agents like perphenazine sit between.
FGAs were largely supplanted as first-line by SGAs because of the EPS burden. They remain in use for specific situations: rapid agitation control (IM haloperidol), Tourette syndrome (pimozide, haloperidol), adherence-limited schizophrenia via long-acting injectables, and cost-constrained settings. The CATIE trial in 2005 challenged the assumption that all SGAs are superior to FGAs — perphenazine performed comparably to several SGAs — but the practical preference for SGAs remains because the EPS trade-off is real.