Benperidol is a typical first-generation antipsychotic. It belongs to the chemical class of butyrophenones, a group of antipsychotics with a similar chemical core of phenylbutyrophenone. Benperidol was first introduced in the late 1950s and was one of the first neuroleptics used to treat psychoses such as schizophrenia.
Benperidol and other typical first-generation antipsychotics work primarily by blocking postsynaptic dopamine D2 receptors, which leads to a decrease in dopaminergic neurochemical transmission. Hyperactivity of dopaminergic neurons and pathways, especially in the mesolimbic system of the brain, is associated with positive psychosis symptoms such as delusions, hallucinations and disorganized thinking. By blocking these dopamine receptors, typical antipsychotics like benperidol can reduce these positive symptoms.
However, benperidol also binds to other neurotransmitter receptors such as 5-HT2A, muscarinic M1, histamine H1 and noradrenaline α1 receptors. These bindings contribute to many of the side effects of benperidol such as extrapyramidal motor disorders, sedation and constipation. Because of these pronounced and distressing side effects, benperidol has largely lost significance in today’s psychiatric practice. It has been replaced by newer atypical antipsychotics that cause fewer side effects.
Although benperidol was a milestone in the treatment of schizophrenia and other psychoses, its clinical applications today are very limited. Its mechanism of action, which primarily involves blocking dopamine receptors, is still important for the antipsychotic effect, but leads to pronounced extrapyramidal side effects. Benperidol remains an important example of first-generation typical antipsychotics, but has been replaced by newer drugs with a more favorable side effect profile.
Benperidol’s effectiveness in reducing positive psychosis symptoms established the dopamine hypothesis of schizophrenia and the principle of using dopamine receptor blockade to achieve an antipsychotic effect. However, its side effects highlight the need for more selective and tailored approaches that avoid excessive blockade of dopamine and other neurotransmitters. Overall, benperidol represents an important step in the development of antipsychotic treatment, but its use today is very limited due to intolerable side effects.