The antipsychotic drugs (neuroleptics) are used in schizophrenia and are also effective in the treatment of other psychoses and agitated states. Older drugs have high affinity for dopamine D2 receptors, whereas newer antipsychotic drugs have greater affinity for serotonin5-HT2 receptors. 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. 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.
The major chemical subgroups of older antipsychotic drugs are the phenothiazines (eg, chlorpromazine, thioridazine, fluphenazine), the thioxanthenes (eg, thiothixene), and the butyrophenones (eg, haloperidol).
Newer "second generation" drugs of varied heterocyclic structure are also effective in schizophrenia, including clozapine, loxapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. In some cases, these atypical antipsychotic drugs may be somewhat more effective and less toxic than the older drugs. However, they are much more costly than standard older drugs, most of which are prescribed generically.
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 many agents (eg, fluphenazine, haloperidol) are available for both rapid initiation of therapy and depot treatment.
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 of untreated schizophrenics. The dopamine hypothesis of schizophrenia is not fully satisfactory because antipsychotic drugs are only partly effective in most patients and because many effective drugs have a much higher affinity for other receptors, including serotonin receptors, than for D2 receptors.
Five different dopamine receptors (D1–D5) have been characterized. Each is G protein-coupled and contains 7 transmembrane domains. The D2 receptor, found in the caudate putamen, nucleus accumbens, cerebral cortex, and hypothalamus, is negatively coupled to adenylyl cyclase. The therapeutic efficacy of the older antipsychotic drugs correlates with their ...