Antipsychotic Agents

ANTIPSYCHOTIC AGENTS

Antipsychotic drugs are able to reduce psychotic symptoms in a wide variety of conditions, including schizophrenia, bipolar disor-der, psychotic depression, senile psychoses, various organic psy-choses, and drug-induced psychoses. They are also able to improve mood and reduce anxiety and sleep disturbances, but they are not the treatment of choice when these symptoms are the primary disturbance in nonpsychotic patients. A neuroleptic is a subtype of antipsychotic drug that produces a high incidence of extrapyra-midal side effects (EPS) at clinically effective doses, or catalepsy in laboratory animals. The “atypical” antipsychotic drugs, are now the most widely used type of antipsychotic drug.

History

Reserpine and chlorpromazine were the first drugs found to be useful to reduce psychotic symptoms in schizophrenia. Reserpine 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 dis-sociation; 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 anti-psychotic drugs towards the use of an ever increasing number of atypical 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 hos-pitalizations. 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 disor-ders 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: the presence of delusions (false beliefs), various types of hallucina-tions, 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 disturbance. 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 disor-der. 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, adop-tion, 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 pre-sentation and course.