A second generation of antipsychotic medications, commonly referred to as "atypical antipsychotics," was introduced in 1998. The term "atypical" refers to an antipsychotic medication that produces minimal extrapyramidal side effects (EPS) at clinically effective antipsychotic doses, has a low propensity to cause tardive dyskinesia (TD) with long-term treatment, and treats both positive and negative signs and symptoms of schizophrenia . Atypical agents currently available include clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify), and paliperidone (Invega), the active metabolite of risperidone.
Atypical antipsychotics have largely replaced traditional agents as first-line therapy in the treatment of schizophrenia. Toxicologic exposures and fatalities associated with atypical agents continue to increase in the United States with 32,422 exposures and 72 deaths in 2003; 38,315 exposures and 94 deaths in 2004; and 43,540 exposures, but only six deaths in 2008 [2-4]. Consequently, it is important for the practicing clinician to be familiar with the pharmacology and toxicology of these medications.
This topic review will discuss the basic pharmacology, presentation, and management of acute intoxication with atypical antipsychotics. Discussions of the clinical use of these drugs, details concerning potential side effects, and general management of drug overdose are found elsewhere. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Neuroleptic malignant syndrome" and "General approach to drug poisoning in adults".)
PHARMACOLOGY AND CELLULAR TOXICOLOGY
The pharmacology of atypical antipsychotic agents is complex. As a general rule, all exhibit dopamine (D2) receptor blockade, similar to first-generation antipsychotics, but with a lower binding affinity . In addition to lower D2 receptor potency and occupancy at therapeutic doses, atypical agents selectively antagonize mesolimbic D2 receptors more so than those in the nigrostriatum and prefrontal cortex. As a result, side effects attributable to nigrostriatal D2 blockade (eg, extrapyramidal symptoms, such as acute dystonia, parkinsonism, akathisia, and tardive dyskinesia) occur less frequently, as do side effects attributable to mesocortical (ie, prefrontal) D2 blockade (eg, neurocognitive impairment and negative symptoms).
Atypical antipsychotics are also serotonin (5-HT) antagonists at the 5-HT2A receptor subtype. This pharmacologic effect mitigates the negative signs and symptoms of schizophrenia by disinhibiting the dopamine system in the nigrostriatum and prefrontal cortex .