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Chapter: Essentials of Psychiatry: Antipsychotic Drugs

Pharmacology of Antipsychotic Agents

First-generation Antipsychotic Agents, Second-generation and Novel Antipsychotic Agents.

Antipsychotic Drugs




Information about antipsychotic drugs and theoretical develop-ments in the treatment of psychosis is rapidly expanding, and more agents with antipsychotic efficacy are being developed. The advent of newer second-generation antipsychotics in the wake of clozapine represents the first significant advances in the pharmacologic treatment of schizophrenia and related psy-chotic disorders, and many clinicians in the USA are prescribing these second-generation antipsychotics as the first-choice agent for acute and maintenance therapy for these illnesses (Buckley, 2001; McEvoy et al., 1999).


Pharmacology of Antipsychotic Agents


First-generation Antipsychotic Agents


The first-generation antipsychotic agents are equally effective in the treatment of psychotic symptoms of schizophrenia, while they vary in potency, their pharmacological properties, and their propensity to induce side effects (Davis et al., 1980; American Psychiatric Association, 2000). The effect that is common to all first-generation antipsychotics is a high affinity for dopamine D2 receptors (Marder and Van Putten, 1995). In addition, all of the first-generation agents produce EPS, including parkinsonism, dystonia, akathisia and TD, to a varying degree and increase serum prolactin concentration in the usual clinical dose range (Meltzer, 1985). These are described in greater detail in the sec-tion “Adverse Effects”.


The first-generation agents are usually classified into three groups: phenothiazines, butyrophenones (e.g., haloperidol) and others (e.g., thiothixene, molindone and loxapine), based on their structure.





The phenothiazine antipsychotics are usually categorized into three classes according to substitutions at position 10 (Marder and Van Putten, 1995). The aliphatic class (e.g., chlorpromazine) consists of agents that have relatively low potency at D2 receptors compared with other first-generation antipsychotics, more an-timuscarinic activity, more sympathetic and parasympathetic ac-tivity, and more sedation. The piperidine class (e.g., thioridazine) has a similar clinical profile to the aliphatic class, with somewhat reduced affinity for D2 sites. The piperazine class (e.g., fluphena-zine) has fewer antimuscarinic and autonomic effects, but greater potency at D2 sites, and thus can produce more EPS.



The butyrophenone antipsychotics, represented by haloperidol, tend to be potent D2 antagonists and have minimal anticholiner-gic and autonomic effects (Marder and Van Putten, 1995). PET studies demonstrate that low doses of haloperidol (2–5 mg/day) would be expected to induce 60 to 80% dopamine D2 receptor occupancy (Kapur et al., 1996, 1997). While theoretically this dosage should be enough for optimal clinical efficacy correlated to an optimal D2 receptor antagonism, dosages five to 20 times as high are prescribed in current clinical practice (Stip, 2000).

Second-generation and Novel Antipsychotic Agents


The pharmacological properties that confer the unique therapeu-tic properties of second-generation antipsychotic drugs are poorly understood despite intensive research efforts by the pharmaceuti-cal industry and the psychopharmacology research community. Since clozapine is the prototype “atypical” drug, defining the role of the individual complex actions of this drug, that are respon-sible for its unique therapeutic profile, is necessary for rational design of new and improved second-generation (clozapine-like) antipsychotics (Miyamoto et al., 2002a).


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