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INTRODUCTION

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The antipsychotic drugs are used in schizophrenia and are also effective in the treatment of other psychoses and agitated states. The efficacy of these drugs has led to several hypotheses linking specific transmitter disorders to the etiology of schizophrenia. Older (first generation) drugs have high affinity for dopamine D2 receptors, thus an early hypothesis postulated a disorder of dopamine transmission as a primary factor. Newer (second generation) antipsychotic drugs (also called atypical antipsychotic drugs) have greater affinity for serotonin 5-HT2 receptors, suggesting that disorders involving this transmitter are pathogenic. Glutamate has also been implicated in some studies.

Although schizophrenia is not cured by drug therapy, the symptoms, including thought disorder, emotional withdrawal, and hallucinations or delusions, may be ameliorated by antipsychotic drugs. Unfortunately, protracted therapy (years) is often needed and can result in severe toxicity in some patients. Bipolar disorder (formerly called manic-depressive disorder) may be related to schizoaffective disorder on a continuum. In bipolar affective disorder, although lithium has been the mainstay of treatment for many years, the use of newer antipsychotic agents and of several antiseizure drugs is increasing. Other indications include Tourette syndrome and some forms of agitated dementia.

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ANTIPSYCHOTIC DRUGS

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A. Classification
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The first generation antipsychotic drugs constitute several chemical subgroups including the phenothiazines (eg, chlorpromazine, thioridazine, fluphenazine), the thioxanthenes (eg, thiothixene), and the butyrophenones (eg, haloperidol).

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The established second generation drugs have varied heterocyclic structures and include clozapine, loxapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. Some very recently approved second generation agents are listed in the Drug Summary table. In some patients, these atypical antipsychotic drugs may be somewhat more effective and are often less toxic than the older drugs. Several are now available in generic form.

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B. Pharmacokinetics
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The antipsychotic drugs are well absorbed when given orally, and because they are lipid soluble, they readily enter the central nervous system (CNS) and most other body tissues. Many are bound extensively to plasma proteins. These drugs require metabolism by liver enzymes before elimination and have long plasma half-lives that permit once-daily dosing. In some cases, other drugs that inhibit cytochrome P450 enzymes can prolong the half-lives of antipsychotic agents. Parenteral forms of some agents (eg, fluphenazine, haloperidol, ziprasidone, olanzapine, and aripiprazole) are available for rapid initiation of therapy, use in uncooperative patients, or depot treatment.

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C. Mechanism of Action
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1. Dopamine hypothesis
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The dopamine hypothesis of schizophrenia proposes that the disorder is caused by a relative excess of functional activity of the neurotransmitter dopamine in specific neuronal tracts in the brain. This hypothesis is based on several observations. First, many antipsychotic drugs block brain dopamine receptors (especially D2 receptors). Second, dopamine agonist drugs (eg, amphetamine, levodopa) exacerbate schizophrenia. Third, an increased density of dopamine receptors has been detected in certain brain regions ...

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