Atypical antipsychotics and movement disorders

The term atypical antipsychotics alludes to the existence of a class of drugs which are supposed to be at least as effective as the old, typical antipsychotics for antipsychotic effect but are less likely to cause severe side effects, especially fewer extrapyramidal symptoms (EPS), including tardive dyskinesia.(1–3) Atypical antipsychotics are also referred to as second-generation antipsychotics. The term atypical antipsychotic met widespread acceptance in the 1990s when clozapine was reintroduced in Europe and North America for the treatment of “treatment-resistant schizophrenia,” that is, schizophrenia not responding to typical, first-generation antipsychotics.(4,5) Two decades earlier, clozapine had already been used as a first-line treatment for schizophrenia, but in 1975, it was withdrawn due to the occurrence of agranulocytosis. Clozapine's mode of action is different from other antipsychotics in that its clinical potency does not correlate with its ability to block dopamine D2 receptors.(4,6) Also, the lower rate of EPS matched the idea of a different mode of action. Subsequently, the “new” and “atypical” mode of action of clozapine was attributed to several new drugs.(1,2) At the moment, the following drugs are considered “atypical” antipsychotic agents: clozapine (marketed as Clozaril), quetiapine (Seroquel), risperidone (Risperdal), olanzapine (Zyprexa), ziprasidone (Geodon), aripiprazole (Abilify), melperone (Buronil), asenapine (Saphris), blonanserin (Lonasen), iloperidone (Fanapt), lurasidone (Latuda), and sertindole (Serdolect). However, there is no universally accepted definition of “atypical” and some of these drugs are clinically indistinguishable in their movement side effects from first-generation antipsychotics. Meltzer, Matsubara, and Lee hypothesized that the favorable clinical characteristic of clozapine, that is, the low risk for EPS, is due to the relatively stronger 5- HT _2A -receptor affinity compared with that for the dopamine D2 receptor.(7) This concept largely contributed to the development of the leading atypical antipsychotics such as risperidone, olanzapine, quetia- pine, and ziprasidone.(6) Aripiprazole is different in this respect because it is a partial dopamine D2 receptor agonist (and thus a weak D2 receptor agonist) and also a 5-HT _2A-antagonist.