CNS Drug Reviews

Schizophrenia is a devastating mental illness which can seriously compromise the lives of those afflicted, as well as their caretakers and family members. Historically, the cause of this illness has been attributed to demonic possession, sinful behavior, bad parenting, or even the season of the year when the subject was born. Various and sundry interventions have been employed over the years to treat this illness including complete social isolation, insulin shock, and electroconvulsive therapy. In 1952, the medication chlorpromazine was discovered to have beneficial effects on the positive symptoms of the illness (e.g., delusions, hallucinations, paranoia), ushering in a new era of development and understanding of the biological basis of schizophrenia. Chlorpromazine was demonstrated to block dopamine (D2) receptors in the brain, leading researchers to speculate that the illness was caused by excessive dopaminergic activity. This crude understanding of the pathophysiology of schizophrenia was to become the foundation of subsequent drug development for many years. Although chlorpromazine represented a major breakthrough in the humane management of the illness, it was also associated with a wide range of adverse effects, including sedation, anticholinergia, orthostasis, extrapyramidal side effects (EPS), and tardive dyskinesia. As these toxic phenomena were believed to be due to action of chlorpromazine on many neurotransmitter systems, drug development focused more intently upon dopaminergic systems, ultimately identifying compounds such as haloperidol and fluphenazine which possessed a high affinity for postsynaptic D2 receptors. Clinically, these medications are less sedating than older compounds and lack anticholinergic effects, but the incidence and severity of EPS is much greater with these agents, resulting in additional discomfort, disability, and medication noncompliance.