FIGURE 29–1 Structural formulas of some older antipsychotic drugs: phenothiazines, thioxanthenes, and butyrophenones. Only representative members of each type are shown.
FIGURE 29–2 Structural formulas of some newer antipsychotic drugs.
A. Phenothiazine Derivatives
Three subfamilies of phenothiazines, based primarily on the side chain of the molecule, were once the most widely used of the antipsychotic agents. Aliphatic derivatives (eg, chlorpromazine) and piperidine derivatives (eg, thioridazine) are the least potent. These drugs produce more sedation and weight gain. Piperazine derivatives are more potent (effective in lower doses) but not necessarily more efficacious. The piperazine derivatives are also more selective in their pharmacologic effects (Table 29–1).
The National Institute of Mental Health (NIMH)-funded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) reported that perphenazine, a piperazine derivative, was as effective as atypical antipsychotic drugs, with the modest exception of olanzapine, and concluded that first-generation antipsychotic drugs are the treatment of choice for schizophrenia based on their lower cost. However, there were numerous flaws in the design, execution, and analysis of this study, leading to it having only modest impact on clinical practice. In particular, it
TABLE 29–1 Antipsychotic drugs: Relation of chemical structure to potency and toxicities.
1Ratio of affinity for D2 receptors to affinity for 5-HT2A receptors. 2At dosages below 8 mg/d.
failed to consider issues such as dosage of olanzapine, inclusion of treatment resistant patients, encouragement of patients to switch medications inherent in the design, risk for tardive dyskinesia following long-term use of even low-dose typical antipsychotics, and the necessity of large sample sizes in equivalency studies.
B. Thioxanthene Derivatives
This group of drugs is exemplified primarily by thiothixene.
C. Butyrophenone Derivatives
This group, of which haloperidol is the most widely used, has a very different structure from those of the two preceding groups. Haloperidol, a butyrophenone, is the most widely used first-generation antipsychotic drug, despite its high level of EPS relative to other typical antipsychotic drugs. Diphenylbutylpiperidines are closely related compounds. The butyrophenones and congeners tend to be more potent and to have fewer autonomic effects but greater extrapyramidal effects than phenothiazines (Table 29–1).
D. Miscellaneous Structures
Pimozide and molindone are first-generation antipsychotic drugs. There is no significant difference in efficacy between these newer typical and the older typical antipsychotic drugs.
E. Second-Generation Antipsychotic Drugs
Clozapine, asenapine, olanzapine, quetiapine, paliperidone, risperidone, sertindole, ziprasidone, zotepine, brexpiprazole, cariprazine, and aripiprazole are second-generation antipsychotic drugs (some of which are shown in Figure 29–2). Clozapine is the prototype. Paliperidone is 9-hydroxyrisperidone, the active metabolite of risperidone. Risperidone is rapidly converted to 9-hydroxyrisperidone in vivo in most patients, except for about 10% of patients who are poor metabolizers. Sertindole is approved in some European countries but not in the USA.
These drugs have complex pharmacology, but they share a greater ability to alter 5-HT2A-receptor activity than to interfere with D2-receptor action. In most cases, they act as partial agonists at the 5-HT1A receptor, which produces synergistic effects with 5-HT2A receptor antagonism. Most are either 5-HT6 or 5-HT7 receptor antagonists.