Atypical antipsychotics—clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole—differ from conventional antipsychotics primarily by virtue of their actions at multiple central receptor sites. Each agent has its own unique receptor profile. The discovery of dopaminergic receptor-blocking capabilities of conventionblockingal antipsychotic drugs led to the dopamine hypothesis of schizophrenia. More recently, the role of serotonergic and other receptors in the pathophysiology and symptomology of schizophrenia and schizoaffective disorder has been identified, and the receptor actions of atypical antipsychotics have been linked to both antipsychotic efficacy and the propensity for extrapyramidal symptoms and other adverse effects. Receptor occupancy is directly related to antipsychotic dose, and the nature of the relationship between clinical utility and receptor occupancy is beginning to emerge. As our understanding of this relationship becomes more clear, the mechanism underlying clinical distinctions between agents will be understood.

Patients with schizophrenia have a 20% shorter lifespan than people without the disorder. An increased risk of cardiovascular morbidity and mortality is also associated with schizophrenia. Atypical antipsychotics may contribute to the prevalence of cardiovascular disease by causing weight gain and increased adiposity, risk of insulin resistance, hyperglycemia, diabetes, and hyperlipidemia. Atypical antipsychotics that produce the greatest degree of weight gain also appear to impose the greatest risk of diabetes and hyperlipidemia. Recent evidence suggests that atypical antipsychotics may even affect glucose and lipid metabolism independent of weight gain. Among the currently marketed antipsychotics, clozapine and olanzapine appear to produce the greatest degree of weight gain. Moderate increases in weight are also observed with quetiapine and risperidone. Only ziprasidone and aripiprazole appear to be weight neutral. Atypical antipsychotics that produce the greatest degree of weight gain also appear to carry the greatest risk of diabetes and hyperlipidemia. Because of the potential for atypical antipsychotics to cause weight gain and adversely affect glucose and lipid metabolism, clinical monitoring of these parameters is critical. Dietary modification and exercise may be critical to addressing antipsychotic-induced weight gain and its consequences. In patients with persistent weight gain, evaluation of the risks and benefits of ongoing medications and consideration of switching to an antipsychotic with lower weight-gain liability may improve health outcomes.