03 - Classification of antipsychotics

Classification of antipsychotics

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 1 ANTIPSYCHOTIC DRUGS General introduction Classification of antipsychotics Before the 1990s, antipsychotics (or major tranquillisers as they were then known) were classified according to their chemistry. The first antipsychotic, chlorpromazine, was a phenothiazine compound – a tricyclic structure incorporating a nitrogen and a sulphur atom. Further phenothiazines were generated and marketed, as were chemically similar thioxanthenes such as flupentixol. Later, entirely different chemical structures were developed according to pharmacological paradigms. These included butyrophenones (haloperidol), diphenylbutylpiperidines (pimozide) and substituted benzamides (sulpiride, amisulpride). Chemical classification remains useful but is rendered somewhat redundant by the broad range of chemical entities now available and by the absence of any clear structure– activity relationships for newer drugs. The chemistry of some older drugs does relate to their propensity to cause movement disorders. Piperazine phenothiazines (e.g. fluphenazine, trifluoperazine), butyrophenones and thioxanthenes are most likely to cause extrapyramidal effects, while piperidine phenothiazines (e.g. pipotiazine) and benzamides are the least likely. Aliphatic phenothiazines (e.g. chlorpromazine) and diphenylbutylpiperidines (pimozide) are perhaps somewhere in between. Relative liability for inducing extrapyramidal side effects (EPSEs) was originally the primary factor behind the typical/atypical classification. Clozapine had long been known as an atypical antipsychotic on the basis of its low liability to cause EPSEs and its failure in animal-­based antipsychotic screening tests. Its remarketing in 1990 signalled the beginning of a series of new medications, all of which were introduced with claims (to varying degrees of accuracy) of ‘atypicality’. Of these medications, perhaps only clozapine, and possibly quetiapine, is completely atypical, seemingly having a Schizophrenia and related psychoses