was used only briefly for this purpose and is no longer of interest as an antipsychotic agent. Chlorpromazine is a neuroleptic agent; that is, it produces catalepsy in rodents and EPS in humans. The discovery that its antipsychotic action was related to dopamine (D or DA)-receptor blockade led to the identification of other compounds as antipsychotics between the 1950s and 1970s. The discovery of clozapine in 1959 led to the realization that antipsychotic drugs need not cause EPS in humans at clinically effective doses. Clozapine was called an “atypical” antipsychotic drug because of this dissociation; it produces fewer EPS at equivalent antipsychotic doses in man and laboratory animals. As a result, there has been a major shift in clinical practice away from typical or first-generation antipsychotic drugs toward the use of an ever-increasing number of atypical or second-generation drugs, which have other advantages as well. The introduction of antipsychotic drugs led to massive changes in disease management, including brief instead of life-long hospitalizations. These drugs have also proved to be of great value in studying the pathophysiology of schizophrenia and other psychoses. It should be noted that schizophrenia and bipolar disorder are no longer believed by many to be separate disorders but rather to be part of a continuum of brain disorders with psychotic features.
Nature of Psychosis & Schizophrenia
The term “psychosis” denotes a variety of mental disorders that are characterized by the inability to distinguish between what is real and what is not: the presence of delusions (false beliefs); various types of hallucinations, usually auditory or visual, but sometimes tactile or olfactory; and grossly disorganized thinking in a clear sensorium. Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking and perceptual disturbance. Schizophrenia is the most common psychotic disorder, present in about 1% of the population and responsible for approximately half of long-term psychiatric hospitalizations. Psychosis is not unique to schizophrenia and is not present in all patients with schizophrenia at all times.
Schizophrenia is considered to be a neurodevelopmental disorder. This implies that structural and functional changes in the brain are present even in utero in some patients, or that they develop during childhood and adolescence, or both. Twin, adoption, and family studies have established that schizophrenia is a genetic disorder with high heritability. No single gene is involved. Current theories involve multiple genes with common and rare mutations, including large deletions and insertions (copy number variations), combining to produce a very variegated clinical presentation and course.
The discovery that indole hallucinogens such as LSD (lysergic acid diethylamide) and mescaline are serotonin (5-HT) agonists led to the search for endogenous hallucinogens in the urine, blood, and brains of patients with schizophrenia. This proved fruitless, but the identification of many 5-HT-receptor subtypes led to the pivotal discovery that 5-HT2A-receptor and possibly 5-HT2C stimulation was the basis for the hallucinatory effects of these agents.