Antipsychotics are a group of drugs that are used to treat a handful of psychiatric disorders characterized by disturbed thought and behavior, most notably schizophrenia. Although they are not curative, they relieve some of the debilitating symptoms of this group of disorders. They are indicated clinically for patients with both acute and chronic schizophrenic symptoms. The "target" symptoms for which antipsychotics appear to be most effective include hallucinations, delusions, tension, hyperactivity, combativeness, insomnia, anorexia, and seclusiveness.

• What are Psychoses?
• History of Antipsychotics
• Behavioral Effects in Humans
• Mechanism of Action
• Thought Questions and Quick Quiz
• Additional Sources of Information

Schizophrenia represents a group of psychiatric disorders characterized by disordered thought and behavior. The symptoms of schizophrenia can be divided into two types, positive and negative. Positive symptoms are those not normally found in healthy individuals, including hallucinations, delusions and thought disorder. Negative symptoms represent the loss of qualities normally present in healthy individuals, including impoverishment of thought, blunted emotion, attention deficit, and lack of motivation or initiative. Schizophrenia is a chronic disorder, typically arising in early adulthood and progressing throughout the rest of the individual's life. Although schizophrenia afflicts a relatively small percentage of the population, approximately 1% over a lifetime, the impact is significant in disruption of families, loss of productivity and a high incidence of suicide and premature death.

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Chlorpromazine was synthesized in 1950 and with it ushered in a new era in the treatment of mental illness. Henri Laborit, a French physician, was using chlorpromazine as a medication to decrease anxiety before surgery. Noting the calming effect of this drug on patients, he suggested that it might be useful in the treatment of mental illness. In Paris in 1951, Laborit tested his theory by administering chlorpromazine to psychotic patients, with striking results. The drug significantly decreased agitation without producing excess sedation or loss of consciousness. Patients became less excitable and their thoughts appeared to become less chaotic. By 1955, word of the successful use of chlorpromazine spread throughout the world and the number of hospitalized psychiatric patients dramatically decreased. Chlorpromazine revolutionized psychiatry and in particular it represented a major turning point in the treatment of severe psychiatric disorders such as schizophrenia. Since chlorpromazine a number of different antipsychotics have been developed. Because of the ability to decrease agitation in profoundly disturbed individuals, antipsychotics have been referred to by some as "major tranquilizers". Another term that has been used to identify these drugs is "neuroleptics", which refers primarily to their motor side effects.

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When administered acutely, antipsychotics produce profound effects in psychotic individuals, including patients with schizophrenia, acute mania, and others displaying agitation, aggression or paranoia. Soon after administration individuals become less agitated, restless, aggressive and impulsive without becoming excessively sedated. Intiative and interest in the environment may be reduced, in addition to displays of emotion or affect. However, while there may be drowsiness and some slowness in response to external stimuli, subjects are easily aroused, capable of giving appropriate answers to direct questions, and seem to have intact intellectual functions. Because of the dramatic tranquilizing effect of these drugs in individuals without schizophrenia, this calming of acute psychosis is less selective than the long-term effects.

With continuous administration of the antipsychotics more selective effects on psychosis emerge. Following two to six weeks of administration, hallucinations, delusions, and disorganized thinking tend to diminish or disappear. Although negative symptoms are less likely to be affected than positive symptoms, patients displaying social withdrawal may sometimes become more responsive and communicative. Antipsychotic drugs are therefore not simply tranquilizers, decreasing the ability of psychotic individuals to express their disturbances, but instead appear to somewhat selectively reverse many of the symptoms of schizophrenia. Antipsychotics do not cure schizophrenia, they simply alleviate symptoms. Since schizophrenia is a lifetime disorder, treatment with antipsychotics typically continues throughout the lifetime of the patient.

Although antipsychotics have produced important benefits in the treatment of mental illness, they are also associated with significant side effects. Acutely, these drugs may produce extrapyramidal symptoms, movement problems similar to Parkinson's Disease. With long-term use these drugs may produce, in some individuals, a disturbing movement disorder known as tardive dyskinesia. Tardive dyskinesia is characterized by stereotypical, repetitive, involuntary movements of the mouth and tongue, trunk, and extremities. These symptoms are typically seen after two years or more of antipsychotic drug use and symptoms sometimes persist indefinitely after discontinuation of the medication. Secondary medications are often administered with antipsychotics to decrease the potential for the development of tardive dyskinesia.

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While the precise mechanism of action that accounts for the effects of antipsychotic medications is still unknown, the dopamine hypothesis is the predominate theory used to explain the action of these drugs. Several years after the discovery of the antipsychotic effects of chlorpromazine it was found that this drug, as well as many other antipsychotics, block dopamine receptors in the brain. This led to the idea that schizophrenia is caused by an excess in dopamine activity in the brain, which is inhibited by blockade of the receptors. Interestingly and importantly, this idea is supported by the observation that high doses of amphetamine, a drug that causes excess release of dopamine in the brain, causes a syndrome indistinguishable from paranoid schizophrenia. Thus, there are two core components to the dopamine theory: (1) psychosis is induced by increased levels of dopamine activity and (2) most antipsychotic drugs block postsynaptic dopamine receptors.

The discovery of different types of dopamine receptors has led to an interest in identifying the dopamine receptor most associated with antipsychotic effects. Early pharmacological studies, which classified dopamine receptors into D1 and D2 receptors, suggested that the D2 receptor was most closely associated with antipsychotic activity. The recognition in recent years through molecular cloning experiments of at least five dopamine receptors has led to an interest in further refining this idea. Evidence suggests that the D4 receptor, which is molecularly and pharmacologically very similar to the D2, may be associated with antipsychotic activity. Of particular note is the fact that the highly effective atypical antipsychotic drug, clozapine, blocks the D4 receptor very efficiently.

Although the dopamine hypothesis has much evidence in support, there are important problems with this idea. Most important is the observation that full therapeutic effects of antipsychotic drugs do not appear until after two to six weeks of administration. It thus appears that it is not the simple blockade of dopamine receptors that is responsible for therapeutic benefits, but perhaps the adaptive response to chronic dopamine receptor blockade.

Antipsychotic Drug	Generic Name	Trade Name
Phenothiazines	Chlorpromazine	Thorazine
	Mesoridazine	Serentil
	Thioridazine	Mellaril
	Fluphenazine	Prolixin
	Perphenazine	Trilafon
	Trifluoperazine	Stelazine
Thioxanthene	Thiothixene	Navane
Dibenzodiazepines	Loxapine	Loxitane
	Clozapine	Clozaril
Benzisoxazole	Risperidone	Risperdal
Butyrophenones	Droperidol	Inapsine
	Haloperidol	Haldol
Indolone	Molindone	Moban
Diphenylbutylpiperidine	Pimozide	Orap

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Thought Questions

• Excessive dopaminergic activity in the mesocorticolimbic dopamine system is thought to be responsible for some of the symptoms of schizophrenia. What are ways that you might you selectively target this dopaminergic system with therapeutic drugs, and not others in the brain?

• What are some potential reasons that antipsychotics take several weeks in order to achieve their full therapeutic effects?

Quick Quiz

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