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Gas chromatography and radioreceptor assay technologies made possible the measurement of nanogram quantities of neuroleptic in the blood. They revealed large differences in blood concentrations among patients receiving the same oral dose. This led to the hope that measuring neuroleptic concentrations would allow more effective oral dosing for individual psychotic patients. Early attempts to study neuroleptic concentration/clinical response patterns, using chlorpromazine, produced confusing results. Many of the studies had serious design flaws, and were complicated by the many active metabolites of chlorpromazine. Adequate blood level/response studies should use fixed drug dosage schedules, drug-responsive patients, and neuroleptics without active metabolites. Brain concentration of drug is probably better reflected by erythrocyte than by plasma concentration. Therefore, recent investigators have usually used erythrocyte haloperidol or butaperazine concentrations to study level/response relationships. These recent studies strongly suggest an "optimal concentration" level/response pattern for haloperidol and butaperazine. Patients tend to respond best to moderate concentrations of neuroleptic, and nonresponse can be due to either too low or too high concentrations. In the latter case, decreasing the oral dose should be seriously considered. Blood level findings remain preliminary. The clinician should continue to fine-tune his clinical skills, using neuroleptic blood concentrations to complement his clinical judgment, in the attempt to determine the lowest effective dose for the individual patient.

Difficulties in developing techniques to measure plasma levels of neuroleptic drugs have included the presence of metabolites, as well as cross-reactivity not only between these metabolites and the parent compound but between drugs (e.g., a phenothiazine and a tricyclic). Although newer techniques have minimized some of these problems, interpretation of published data must also recognize such design limitations as variable dose, small sample size, etc. The literature is reviewed on the relationship between therapeutic response and plasma levels of chlorpromazine, thioridazine, thiothixene, fluphenazine, butaperazine, and haloperidol. It is suggested that additional studies, carefully designed, on dosage and plasma levels could help in achieving the lowest possible therapeutic dosage and thus in minimizing side effects.

Plasma chlorpromazine measured by a gas chromatographic procedure was found to disappear rapidly during the first week after withdrawal of chlorpromazine treatment in a group of 17 chronically hospitalized patients. The drug or its metabolites were no longer measurable in plasma after 8 days.

Plasma chlorpromazine (CPZ) levels were studied in children 8 to 15 yr of age who were receiving CPZ for mental disorders. The results showed that children need larger doses of CPZ than adults to attain comparable plasma concentrations. The apparent therapeutic plasma concentration in children (40 to 80 ng/ml) is lower than that reported for adults (50 to 300 ng/ml). In the children studied, the plasma concentrations declined despite maintained dosage, possibly because of autoinduction of CPZ metabolism. Doses of 6 to all mg/kg body weight, and even as much as 850 mg/day, were tolerated without significant side effects when administered in divided doses 3 or 4 times a day, while doses of less than 6 mg/kg/day frequently failed to produce the desired plasma CPZ levels.