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The effects of high doses of haloperidol on clinical status and plasma neuroleptic and prolactin concentrations and CSF levels of homovanillic acid (HVA) and gamma-aminobutyric acid (GABA) were investigated in three paranoid schizophrenic patients over six weeks. The patients had been receiving haloperidol. Oral dosages were increased at weekly intervals from 10 to 200 mg/day and then reduced to 10 mg/day. The increase did not affect paranoid symptoms. Neurological side effects were slightly increased in two patients and moderately reduced in one. Plasma prolactin levels, initially high, increased when the dosage was increased to 100 mg/day but did not increase further. The CSF levels of HVA and GABA increased to day 7 but returned to initial values on day 28 in two patients; they were decreased to day 28 in one patient.

The behavioural effects of both apomorphine (stereotypies) and haloperidol (catalepsy and reversal of stereotypies) were significantly enhanced in hypophysectomized rats compared with sham-operated rats. Both the efficacy and duration of action were increased Hypophysectomized animals had significantly greater brain haloperidol concentrations than did sham-operated animals. The data suggest that changes in brain drug concentrations following hypophysectomy at least partially explain the behavioural alterations seen in this test situation.

Monitoring of haloperidol plasma levels during long-term treatment is not commonly practised in adults and even less in children. In this study, haloperidol plasma levels were measured in children and teenagers with psychotic episodes or abnormal movements. Steady state concentrations ranged from 0.7 to 19 ng/ml. They were apparently unrelated to the doses administered (15-285 micrograms/kg/day), and variations of up to 15-fold were observed with the same dosage. In contrast, a significant correlation (p less than 0.02) was determined between age and dose-concentration ratio. Side-effects also seemed to be significantly related to plasma levels (p less than 0.01); they occurred at concentration higher than 6 ng/ml. Therapeutic response was observed with plasma concentrations of 1 to 4 ng/ml in cases with abnormal movements, but no dose-effect relationship was found in patients with psychotic episodes.

The effect of high doses of haloperidol on the clinical status, plasma neuroleptic and prolactin concentrations as well as on CSF HVA and GABA levels was investigated in 3 paranoid schizophrenic patients over a 6 weeks period. When the study was initiated patients had been on haloperidol (10 mg a day) for 4-10 weeks. Oral doses were increased at weekly intervals from 10 (day 0) to 100 (day 7) and 200 (days 14 to 28) mg a day and then reduced to 100 (day 35) and 10 (day 42) mg/day. A linear relationship was observed between plasmatic levels and daily doses of haloperidol. In neither patient, the increase in haloperidol dosage affected paranoid symptoms. Neurological side effects were slightly increased in 2 cases and moderately reduced in one case. Prolactin plasma levels, already high at the onset of the study rose when increasing the dose to 100 mg a day but did not increase further despite increment in the haloperidol dosage. CSF levels of HVA and GABA rose from day 0 to day 7 but were back to the initial values on day 28 in 2 patients and were decreased from day 0 to day 28 in one patient. For the 3 patients a close correlation was observed between changes in CSF HVA and GABA levels. It is concluded that high doses of haloperidol, although causing biochemical changes compatible with the occurrence of dopamine target cell supersensitivity, do not lead to any clinical improvement in the 3 studied schizophrenic patients.

Haloperidol plasma concentrations were determined in psychotic patients to whom the drug was given by three different routes of administration (i. v. perfusion, intramuscularly and orally). When measured 15 hours after the last administration, a significant difference (p < 0,001) was found in the steady state plasma concentration between the oral and the i.m. route. The values were higher after intramuscular administration and were subject to less interindividual fluctuation than after the oral. The reduction in plasma levels after oral administration in respect to i.m. were in accordance with the bioavailability of haloperidol. The opportunity of switching from oral to intramuscular treatment is discussed.

A sensitive gas-chromatographic method for quantitative analysis of haloperidol in human plasma is described. The use of nitrogen-phosphorus selective detection reduces the time required for analysis. Azaperone is used as the internal reference standard. The method is suitable for the determination of haloperidol plasma levels in patients treated with doses ranging from 1.2 to 200 mg/day. No interference from drugs needed in the associated antipsychotic therapy has been found. The simplicity, specificity and sensitivity of the method make it suitable for routine analysis of haloperidol plasma levels in psychotic patients undergoing chronic treatment.

Plasma levels of haloperidol were monitored in children and teenagers suffering from psychotic episodes and/or abnormal movements (tics and Gilles de la Tourette's syndrome). Steady-state concentrations of haloperidol ranged from 0.7 to 19 ng/ml without any apparent relationship with the administered dose (15--285 micrograms/kg/day) and a 15-fold variability was observed for the same daily dosage. On the contrary, a significant (p < 0.02) relationship was found between the age of the patients and the plasma concentrations to dose ratios, lower values being present in younger patients. Side effects too appeared to be related to plasma levels, with a significant increase (p < 0.01) in incidence for concentrations over 6 ng/ml. In most of the cases suffering from tics and Gilles de la Tourette's syndrome, a positive response was associated with plasma levels of 1--4 ng/ml, while no relationship could be established for the psychotic group. The relevance of monitoring plasma drug levels when prescribing haloperidol in pediatrics is discussed.

The available data on haloperidol pharmacokinetics and haloperidol plasma level monitoring in neuropsychiatric patients are reviewed and compared with authors' personal observations. It appears that although haloperidol disposition can be described by linear kinetics in volunteers, this is not the case in patients in whom a 7--10-fold variability in plasma levels is observed for the same dosage together with the possibility of saturation kinetics and/or first pass effect. Anticholinergics may interfere with haloperidol absorption, and significant differences in disposition rate and binding have been observed in children and cirrhotic patients. A clear correlation appears to exist between plasma concentrations and side effects or adverse reactions with threshold levels for extrapyramidal syndromes of 6--9 ng/ml. Threshold levels for therapeutic effects vary with syndromes and age. In Gilles de la Tourette syndrome, active levels are of the order of 1--3 ng/ml, whereas in psychotic syndromes levels of 10--15 ng/ml are requested. In mania, a good therapeutic effect has been observed with plasma levels of 2.5--4.5 ng/ml. In general, children require lower plasma levels for the same therapeutic effects. In chronic unresponsive schizophrenic patients, poor drug bioavailability is not the major factor for the lack of response, and the possibility that these patients constitute a nosological subgroup is suggested. Therapeutic drug monitoring of haloperidol appears justified because (a) no direct relationship exists between daily doses and haloperidol steady-state plasma levels; (b) there is a possibility of saturation kinetics at higher doses; (c) commonly associated drugs or diseases may alter the kinetic profile of the drug; (d) drug disposition is faster in children than in adults; (e) optimal plasma concentration appears to differ in various pathological syndromes and age groups; and (f) side-effects and adverse reactions are clearly related to haloperidol plasma levels.