Introduction: What makes an antipsychotic atypical?

T spectives on this issue tend to define this term differently. To a pharmacologist, it can mean “serotonin-2A (5-HT2A)–dopamine-2 (D2) antagonist” or “multiple simultaneous neurotransmitter binding activities.” To a prescriber, it can mean “low extrapyramidal symptoms” or “reduction of negative symptoms.” To a marketeer, it may mean “new and different.” To a formulary committee with a short-term orientation, an atypical antipsychotic often means “expensive,” but to a pharmacoeconomist with a long-term orientation, it can mean “cost-effective.” Each of these aspects of atypical antipsychotics is discussed in the articles that are included here. Elliott Richelson, M.D., provides an overview of the pharmacologic binding activities, and other activities, that may define an atypical antipsychotic, including antagonism of 5-HT2A receptors and D2 receptors. He has also discovered, and reports here for the first time, that loxapine and its hydroxylated and demethylated metabolites are all serotonin-dopamine antagonists with higher affinities for 5HT2A receptors than for D2 receptors. Gary Remington, M.D., Ph.D., F.R.C.P.C., and Shitij Kapur, M.D., Ph.D., F.R.C.P.C., review the positron emission tomography (PET) evidence for the in vivo binding characteristics of a number of antipsychotic drugs, from the prototypical conventional antipsychotic haloperidol to the atypical antipsychotics clozapine, risperidone, olanzapine, and quetiapine to the serotonin-dopamine antagonists loxapine and amoxapine. They debate the evidence for the potential clinical relevance of varying amounts of occupancy of 5-HT2A receptors and D2 receptors by all 7 of these drugs. Larry Ereshefsky, Pharm.D., then applies the pharmacologic and pharmacokinetic considerations raised in the articles by Dr. Richelson and by Drs. Remington and Kapur to the selection of an antipsychotic drug. He places loxapine midway in the pharmacologic spectrum from haloperidol to risperidone. I review 5 different serotonin-dopamine antagonists, namely, clozapine, risperidone, olanzapine, quetiapine, and loxapine, and assess whether they are atypical, providing clinical pearls and dosing tips for all 5. This review combines the empirical evidence from clinical practice experience with guidelines from clinical trials as a strategy for selecting an antipsychotic drug. In my analysis, I conclude that loxapine is unusual, but not atypical, and may have a niche for use as an augmenting agent to atypical antipsychotics in patients with unsatisfactory treatment responses.