Reduced haloperidol plasma concentration and clinical response in acute exacerbations of schizophrenia

Twenty-nine hospitalized patients suffering acute exacerbations of schizophrenia were treated for 2 weeks with fixed daily oral doses of haloperidol prospectively calculated to achieve a haloperidol plasma concentration of either 8–18 ng/ml or 25–35 ng/ml. Reduced haloperidol as well as haloperidol concentrations were assayed to determine if the former enhanced the predictability of response. Week 2 haloperidol plasma concentrations were negatively correlated to clinical response as measured by the percentage change in the BPRS score from baseline (r=–0.43,P<0.05). In contrast, week 2 plasma concentrations of reduced haloperidol, total haloperidol (haloperidol+reduced haloperidol), and reduced haloperidol/haloperidol ratio did not correlate with the change in the BPRS score. Chi-square analysis concluded that patients with ratios greater than one were no less likely to be treatment responders (<25% improvement in BPRS from baseline and week 2 BPRS <55) than those with ratios less than one. Although these data lend additional support to reports of a curvilinear relationship between haloperidol plasma concentration and clinical response, they also suggest that reduced haloperidol plasma concentrations are of no value in predicting treatment response.From the Mental Health Research Center — Major Psychoses, funded in part by NIMH Grant #5 P50 MH43271     

Serum haloperidol concentrations and clinical response in acute psychosis

Steady state serum haloperidol concentrations measured by gas-liquid chromatography and a neuroleptic radioreceptor assay were compared to clinical response in 21 acutely psychotic inpatients. Serum concentrations measured by the two assay methods correlated well with each other, although the neuroleptic radioreceptor assay was much less sensitive. There was also a significant linear relationship between haloperidol dose (mg/kg/day) and steady state serum concentration. The correlation between haloperidol serum concentrations and clinical response after 2 to 3 weeks was nonlinear and most pronounced in the intermediate range (15 to 40 ng/ml). Further studies will be needed to establish with certainty the existence and exact limits of a therapeutic window.     

Serum neuroleptic concentrations and clinical response: A radioreceptor assay investigation of acutely psychotic patients

Twenty-two acutely psychotic patients were rigorously assessed for psychopathology at baseline and after 14 days of neuroleptic treatment. The neuroleptic radioreceptor assay (NRRA) was used to determine serum neuroleptic concentrations. Serum neuroleptic concentration was significantly, nonlinearly related to changes in BPRS Total Score, and BPRS Factor Scores for Thought Disturbance and Anxiety-Depression. Clinical improvement was associated with intermediate (11–50, 51–126 ng/ml haloperidol equivalents) while poor clinical outcome was related to both low (less than or equal to 10 ng/ml) or high (greater than 125 ng/ml) serum levels. The results are discussed in terms of a possible therapeutic window for the neuroleptics and the implications this might have for clinical practice.     

Comparative efficacy of red cell and plasma haloperidol as predictors of clinical response in schizophrenia

The relative utility of steady-state (SS), plasma (Pl), and red blood cell (RBC) haloperidol levels for predicting clinical response was evaluated in a fixed-dose study in schizophrenic inpatients. There were significant curvilinear relationships between the decrease in BPRS Psychosis Factor Scores by day 24 of haloperidol treatment and both Pl (R²=0.34) and RBC (R²=0.38) haloperidol levels. Although SS RBC haloperidol levels consistently showed a slightly stronger relationship to clinical response than Pl levels. in several comparisons, the differences in R²s between Pl and RBC haloperidol were not statistically significant. Ninety percent confidence intervals for the blood level ranges associated with optimal clinical response in our sample of patients were: 6.5–16.5 ng/ml Pl haloperidol and 2.2.–6.8 ng/ml RBC haloperidol.     

Neuroleptic radioreceptor activity and clinical outcome in schizophrenia

The relationship between serum haloperidol concentration and clinical response was examined in 27 schizophrenic inpatients between the ages of 18 and 56 years. All patients were treated with haloperidol, 20 mg/day for the first 2 weeks. Dosage adjustment after 2 weeks of treatment was made in seven subjects based on poor clinical response or side effects. Haloperidol activity was determined by the radioreceptor assay for neuroleptics on weeks 2 and 4 serum samples. The results indicated that higher radioreceptor activity levels, particularly above 22 ng/ml, were associated with poorer clinical response. The data suggest that radioreceptor activity levels are not at a steady state after 2 weeks drug treatment. Additionally, problems secondary to low sensitivity of the radioreceptor assay may limit its utility at low serum concentrations.     

Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics

Rationale: Monitoring plasma clozapine concentrations may play a useful role in the management of patients with schizophrenia, but information on the relationship between the plasma levels of the drug and response is still controversial. Objective: The purpose of this study was to assess the relationship between plasma concentrations of clozapine and its weakly active metabolite norclozapine and clinical response in patients with schizophrenia resistant to conventional neuroleptics. Methods: Forty-five patients, 35 males and ten females, aged 19–65 years, were given clozapine at a dosage up to 500 mg/day for 12 weeks. Steady-state plasma concentrations of clozapine and norclozapine were measured at week 12 by a specific HPLC assay. Psychopathological state was assessed at baseline and at week 12 by using the Brief Psychiatric Rating Scale, and patients were considered responders if they showed a greater than 20% reduction in total BPRS score compared with baseline and a final BPRS score of 35 or less. Results: Mean plasma clozapine concentrations were higher in responders (n=18) than in non-responders (n=27) (472±220 versus 328±128 ng/ml, P<0.01), whereas plasma norclozapine levels did not differ between the two groups (201±104 versus 156±64 ng/ml, NS). A significant positive correlation between plasma levels and percent decrease in total BPRS score was found for clozapine (r _s=0.371, P<0.02), but not for norclozapine (r _s=0.162, NS). A cutoff value at a clozapine concentration of about 350 ng/ml differentiated responders from non-responders with a sensitivity of 72% and a specificity of 70%. At a cutoff of 400 ng/ml, sensitivity was 67% and specificity 78%. The incidence of side effects was twice as high at clozapine concentrations above 350 ng/ml compared with lower concentrations (38% versus 17%). Conclusions: These results suggest that plasma clozapine levels are correlated with clinical effects, although there is considerable variability in the response achieved at any given drug concentration. Because many patients respond well at plasma clozapine concentrations in a low range, aiming initially at plasma clozapine concentrations of 350 ng/ml or greater would require in some patients use of unrealistically high dosages and imply an excessive risk of side effects. Increasing dosage to achieve plasma levels above 350–400 ng/ml may be especially indicated in patients without side effects who failed to exhibit amelioration of psychopathology at standard dosages or at lower drug concentrations. Received: 5 May 1999 / Final version: 30 August 1999     

Lack of significant pharmacokinetic interaction between haloperidol and grapefruit juice

The effects of repeated ingestion of grapefruit juice, an inhibitor of cytochrome P4503A4 (CYP3A4), on the steady-state plasma concentrations of haloperidol and reduced haloperidol were examined. Twelve schizophrenic inpatients receiving haloperidol 12 mg/day, ingested grapefruit juice 600 ml/day for 7 days. Blood samples were collected before and during grapefruit juice coadministration and 1 week after its discontinuation together with an assessment of clinical status. Plasma drug concentrations were measured using high-performance liquid chromatography. Clinical status for each patient was assessed by the Brief Psychiatric Rating Scale (BPRS) and the UKU side-effect rating scale (UKU). Plasma concentrations of haloperidol and reduced haloperidol during grapefruit juice coadministration (9.0 +/- 3.0 and 2.6 +/- 1.4 ng/ml, respectively) were not significantly different from those before grapefruit juice coadministration (9.1 +/- 2.8 and 2.6 +/- 1.5 ng/ml) or those 1 week after its discontinuation (8.8 +/- 2.7 and 2.6 +/- 1.3 ng/ml). There was no change in the scores of BPRS or UKU during the study period. The present results shows that grapefruit juice does not affect the plasma concentrations of haloperidol and reduced haloperidol or clinical status in patients receiving haloperidol.     

Disposition of haloperidol pyridinium and reduced haloperidol pyridinium in schizophrenic patients: no relationship with clinical variables during short-term treatment

In an open clinical trial, serum concentrations of haloperidol pyridinium (C(HP+)) and reduced haloperidol pyridinium (C(RHP+)), as well as haloperidol (CH) and reduced haloperidol (C(RH)), were measured in 57 schizophrenic and schizoaffective inpatients during 6 weeks of short-term treatment. Psychopathology was monitored with the Brief Psychiatric Rating Scale (BPRS), and extrapyramidal adverse effects were assessed with the Extrapyramidal Symptom Rating Scale (EPS). Significantly linear relationships were found between haloperidol dose (D) and pyridinium metabolite serum concentrations, as well as between C(H) and the pyridinium metabolite serum concentrations. C(HP+) (range, 0.2-4.9 ng/mL) and C(RHP+) (range, 0.03-6.23 ng/mL) were low compared with C(H) and C(RH), being as mean values approximately 7% and 14% of C(H) and C(RH), respectively. Additionally, the values of C(RHP+) and the slope of the correlation of C(H) with the C(RHP+)/C(HP+) ratio were considerably lower than in a previous report of long-term treatment with haloperidol. This is explained by the shorter time of treatment of the present study. Carbamazepine comedication was found to not influence relative pyridinium metabolite serum concentrations C(HP+)/D and C(RHP+)/D. However, the aromatization ratios of haloperidol (C(HP+)/C(H)) and reduced haloperidol (C(RHP+)/C(RH)) were increased by concomitant carbamazepine. As the main result, no relationships between the pyridinium metabolite serum concentrations and clinical variables (BPRS change, EPS, dose of biperiden) were detected. For instance, the aromatization ratios C(HP+)/C(H) and C(RHP+)/C(RH) did not predict clinical improvement or extrapyramidal adverse effects. Therefore, no confirmation of the "pyridinium hypothesis," which suggests haloperidol pyridinium metabolites to be the origin of adverse effects and decreased therapeutic effect, can be derived from this study. However, the authors emphasize that pyridinium metabolites cannot be excluded as the origin of decreased therapeutic effect in long-term treatment and of adverse effects not investigated in the present study, such as tardive dyskinesia. Finally, it is concluded that the serum concentration of the parent drug remains the main variable of interest in the therapeutic drug monitoring of haloperidol during short-term treatment.     

Olanzapine plasma concentrations and clinical response: acute phase results of the North American Olanzapine Trial

Olanzapine is an atypical antipsychotic that is effective in the treatment of schizophrenia. Olanzapine plasma concentrations > or = 9.3 ng/mL (24 hours postdose) have been identified as a predictor of clinical response in acutely ill patients with schizophrenia. The authors report a receiver operating characteristic (ROC) curve analysis of 12-hour olanzapine concentrations and treatment response from the North American Double-Blind Olanzapine Trial. After a 4- to 7-day placebo lead-in, patients meeting DSM-III-R criteria for schizophrenia were randomly assigned to receive olanzapine, haloperidol, or placebo. Patients who were randomly assigned to receive olanzapine were given daily doses ranging from 2.5 to 17.5 mg/day for up to 6 weeks. Blood samples for the determination of olanzapine plasma concentrations were obtained between 10 and 16 hours (11.7 +/- 1.7 hours) after the last dose was administered. Therapeutic response data and olanzapine concentrations used for analysis were obtained from the endpoint visit for each patient if the patient had been receiving a fixed olanzapine dose for at least the last 2 weeks of the study. Plasma concentrations from previous visits were used if endpoint concentrations were invalid. Response was defined as a > or = 20% reduction in Brief Psychiatric Rating Scale (BPRS) scores and a Clinical Global Impression (CGI) Severity scale score of < or = 3 or a final BPRS score of < or = 35. The final ROC analysis included data from 84 patients and suggested an olanzapine concentration > or = 23.2 ng/mL to be a predictor of therapeutic response. Fifty-two percent of patients with 12-hour olanzapine concentrations > or = 23.2 ng/mL responded, whereas only 25% of patients with concentrations < 23.2 ng/mL responded. Furthermore, an olanzapine concentration > or = 23.2 ng/mL was a predictor of response in the Scale for the Assessment of Negative Symptoms (> or = 20% decrease and endpoint CGI < or = 3). Olanzapine concentrations were found to be a function of olanzapine dose (in milligrams per day) and gender such that prospective olanzapine dosing is feasible. A 12-hour olanzapine plasma concentration of > 23.2 ng/mL was a predictor of therapeutic response in acutely ill patients with schizophrenia. Males required a higher olanzapine dose to reach this threshold concentration than their female counterparts.     

Comparison of prolactin concentrations between haloperidol and risperidone treatments in the same female patients with schizophrenia

The present study aimed to investigate intraindividual changes in plasma prolactin concentrations by switching from haloperidol treatment to risperidone treatment. The subjects were 15 female schizophrenic inpatients who received firstly haloperidol 12 mg/day for at least 2 weeks and, thereafter, risperidone 6 mg/day. Prolactin concentration in plasma during risperidone treatment (median 87.5 ng/ml, range 5.3-298.1 ng/ml) was significantly ( P<0.01) higher than during haloperidol treatment (median 50.7 ng/ml, range 11.6-226.6 ng/ml). In contrast, the ratio of prolactin concentration to nmol/l unit drug concentration (the active moiety: the sum of risperidone and 9-hydroxyrisperidone) during risperidone treatment (median 1.10, range 0.02-3.73) was significantly lower ( P<0.001) than that of haloperidol (median 1.81, range 0.41-8.24). Prolactin concentrations during both treatment phases correlated well in individuals (r=0.619, P<0.05), whereas better correlation was found in the ratio of prolactin concentration to drug concentration (r=0.779, P<0.01). These findings suggest the higher risk of hyperprolactinemia during risperidone treatment than during haloperidol treatment at clinically used dosages. However, from a purely pharmacological point of view, prolactin response per drug concentration was more sensitive during haloperidol treatment than risperidone treatment, probably resulting from the potent and selective antagonistic effect of haloperidol on dopamine D(2) receptor, compared with the broader pharmacological spectrum of risperidone.     

Serum prolactin as a correlate of clinical response to haloperidol.

The rise in serum prolactin concentration in patients treated with neuroleptic drugs is well documented, but attempts to relate this rise to clinical response have yielded conflicting results. These conflicting results could be explained by design flaws in those studies attempting to relate prolactin to clinical response. Seventy-three newly (re)admitted drug-free schizophrenic men were randomly assigned to receive haloperidol either 5, 10, or 20 mg daily for 4 weeks. Prolactin levels post-treatment were significantly (p less than 0.02) related to global outcome by logistic regression. A serum prolactin level may be a useful guide to the lowest effective dose of haloperidol in newly treated schizophrenic men. Above a plasma prolactin level of approximately 30 ng/ml there was very little increase in response. Patients on the 5, 10, and 20 mg daily haloperidol doses had mean prolactin levels of 16, 32, and 34 ng/ml, respectively.     

Haloperidol blood levels and effects in schizophrenia and schizoaffective disorder: a progress report

To test the hypothesis of a "therapeutic window," we have randomly assigned acutely exacerbating schizophrenic or schizoaffective patients to one of three plasma levels of haloperidol (HAL): 2-13, 13.1-24, or 24.1-35 ng/ml. Patients who did not improve after 6 weeks of this treatment were randomly assigned to one of the three haloperidol levels for another 6 weeks. The improvement was defined as at least 50 percent reduction of the Brief Psychiatric Rating Scale (BPRS) total score. The results obtained in 111 patients do not support any consistent relationship between plasma level of haloperidol and clinical improvement. Patients in the high haloperidol plasma range tended to have more side effects. These results suggest that the haloperidol doses used in clinical practice may be higher than necessary.     

Haloperidol plasma levels and acute clinical change in schizophrenia

Twenty-five inpatients with acute exacerbations of schizophrenia (by Research Diagnostic Criteria) or schizoaffective disorder underwent a prospective haloperidol dosing procedure and were assigned fixed doses chosen to yield a distribution of haloperidol plasma levels above and below a hypothesized upper therapeutic limit of 18 ng/ml. Changes in Brief Psychiatric Rating Scale scores after 1 week of treatment were negatively correlated with haloperidol plasma levels, and the statistically optimum cutoff point fell near the predicted 18 ng/ml. Plasma level/response relationships over the subsequent 3 weeks were weaker but patients with higher plasma levels had consistently less improvement.     

Serum level monitoring and therapeutic effect of haloperidol in schizophrenic patients

Haloperidol serum concentrations were determined after IM or oral treatment in 15 schizophrenic patients. No correlation was found between drug levels and therapeutic effect. However, a good relationship was found between the half-life calculated after the first IM injection and the BPRS decrease after 3 weeks. Therefore a serum level study on the first day may forecast the therapeutic response.     

Stability of serum neuroleptic and prolactin concentrations during short- and long-term treatment of schizophrenic patients

The potential importance of neuroleptic activity measures in the management of schizophrenia warrants attention to the methods for assessing neuroleptic bioactivity and stability of neuroleptic bioactivity over time. We have carried out measurements of serum neuroleptic and prolactin concentrations in 18 schizophrenic patients treated with haloperidol or thioridazine for up to 1 year. Serum neuroleptic levels were measurd by a radioreceptor assay using porcine striatum. The lower limit of sensitivity of the assay was 0.6 ng haloperidol/ml, the intra- and interassay coefficients of variation 3 and 9%, respectively. A linear correlation was observed between haloperidol dose (5–30 mg/d) and serum neuroleptic activity (r=0.706, P<0.001) and a curvilinear relationship between thioridazine dose (50–600 mg/d) and serum neuroleptic activity in schizophrenic outpatients. There was a positive correlation between serum neuroleptic and prolactin concentrations for the patients taking haloperidol (r=0.620, P<0.001) or thioridazine (r=0.542, P<0.001). In patients taking a constant dose of haloperidol or thioridazine for up to 1 year serum neuroleptic activity remained stable, suggesting the absence of metabolic tolerance; the observation of a decrease of 38±16% (mean ± SD) in serum prolactin concentrations in patients treated with haloperidol but no prolactin decrease with thioridazine suggests that under certain neuroleptic treatment conditions a functional tolerance develops in the tuberoinfundibular dopamine system.     

Haloperidol plasma level monitoring in pediatric patients

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.     

Plasma level monitoring of antipsychotic drugs. Clinical utility

The steady-state plasma concentrations of antipsychotic drugs show large interpatient variations but remain relatively stable from day to day in each individual patient. Monitoring of antipsychotic drug concentrations in plasma might be of value provided the patients are treated with only 1 antipsychotic drug. Some studies have reported a relationship between therapeutic response and serum antipsychotic drug 'concentrations' as measured using the radioreceptor assay (RRA) method, which measures dopamine receptor-blocking activity in plasma. Most studies, however, have failed to demonstrate such a relationship, and the RRA does not seem to provide the generally useful tool for plasma concentration monitoring of antipsychotic drugs that was hoped for initially. A lack of correlation between dopamine receptor-blocking activity in plasma and therapeutic response may be due to differences in the blood-brain distribution of both antipsychotic drugs and their active metabolites. Chemical assay methods (e.g. GLC and HPLC) have been used in studies which examined the relationships between therapeutic response and antipsychotic drug concentrations in red blood cells and in plasma. It seems that for these drugs, measuring red blood cell concentrations does not offer any significant advantage over measuring plasma concentrations. Reasonably controlled studies of plasma concentration-response relationships using randomly allocated, fixed dosages of chlorpromazine, fluphenazine, haloperidol, perphenazine, sulpiride, thioridazine and thiothixene have been published but often involve relatively few patients. A correlation between therapeutic response and plasma concentrations of thioridazine and its metabolites has not been demonstrated, and plasma level monitoring of thioridazine and its metabolites therefore appears to have no clinical value. Clinical behavioural deterioration concomitant with high plasma concentrations of chlorpromazine and haloperidol have been reported. A dosage reduction might be considered after 2 to 4 weeks' treatment in non-responders who have plasma chlorpromazine concentrations above 100 to 150 micrograms/L or plasma haloperidol concentrations above 20 to 30 micrograms/L. Non-responders and good responders to chlorpromazine treatment, however, have plasma drug concentrations in the same range, and a therapeutic range of plasma chlorpromazine levels has not been defined. Therapeutic plasma haloperidol concentrations (i.e. 'window') in the range of 5 to 20 micrograms/L have been reported by some investigators, but others have found no such relationship.(ABSTRACT TRUNCATED AT 400 WORDS)     

Correlation between pharmacokinetics and clinical effects of ergotamine in patients suffering from migraine

Summary The systemic availability of ergotamine after a single therapeutic oral or rectal dose was studied using a radioimmunoassay during the headachefree state in 24 patients suffering from migraine. Plasma concentrations of the drug were compared with anamnestic data about its clinical effects in the same patients. Among 12 patients with a good therapeutic response to medication, the mean plasma ergotamine levels stayed in the range 0.20 to 0.50 ng/ml for 6h. Their mean plasma levels at 30 min (0.33ng/ml) and 1h (0.40ng/ml) were significantly higher than those (0.06 and 0.08ng/ml, respectively) in 9 patients with only a moderate therapeutic response. In 9 patients with a moderate and 3 with a poor therapeutic response, the mean plasma level generally stayed below 0.10ng/ml. The mean peak concentrations in moderate (0.13 ng/ml) and poor (0.11ng/ml) responders appeared later (at 3h) than in good responders (at 1h). Side effects of the medication appeared to be associated with relatively low plasma levels of ergotamine and also with delayed maximum plasma concentrations of the drug. The present results suggest that the time of the maximum plasma drug level is an important determinant of the clinical effects of ergotamine, and that a good therapeutic response may be expected if a plasma ergotamine level of 0.20ng/ml or more is achieved within 1 hour after oral or rectal administration.Some of the results were previously presented at the 3rd International Migraine Symposium in London, September 17–18, 1980.     

Therapeutic drug monitoring of risperidone using a new, rapid HPLC method: reappraisal of interindividual variability factors

Because of the enormous gap between premarketing studies in physically healthy subjects and clinical practice in patients, the present study reconsidered interindividual variability factors affecting risperidone concentrations under routine therapeutic drug monitoring conditions. The study included 92 patients, 27% of whom were 70 years or older. The patients received risperidone orally (dose range, 0.5-11 mg per day) and had concentrations of risperidone and the active metabolite 9-hydroxyrisperidone measured at steady state by a new, rapid, and sensitive method of high-performance liquid chromatography (HPLC). After normalization to a dose of 4 mg/day, median concentrations were 2.9 ng/ml (80% range, 0.9-27.9 ng/ml) for the parent compound and 24.1 ng/ml (80% range, 12.0-57.6 ng/ml) for the metabolite. When considering linear regression models, age was identified as a major source of interindividual variability, with expected increases of 340% and 220% for concentrations of parent compound and metabolite, with age increasing from 20 to 80 years. Body weight provided an additional significant contribution to the variability of 9-hydroxyrisperidone concentration, a 20-kg higher body weight associated with a concentration decrease of 23%. Serotonin-specific reuptake inhibitor (SSRI) comedication (fluoxetine, two patients; citalopram, two patients; paroxetine, one patient; fluvoxamine, one patient) was significantly associated with 4.6-fold higher concentrations of parent compound, in keeping with an inhibitory action on CYP2D6 enzyme. Significantly higher concentrations of 9-hydroxy-risperidone (+ 29%) were also observed in the 17 patients with biperiden comedication. Therapeutic drug monitoring data, collected in patients representative of the population for which the drug was intended, allowed us to quantify the dose reduction needed in elderly patients and thus provided valuable information in addition to the one collected during premarketing studies performed with strict inclusion and exclusion criteria.     

Neuroleptic monitoring: relation between antipsychotic efficiency and radioreceptor assay of serum haloperidol

Objective: We report preliminary results from use of a radioreceptor assay (RRA) to measure serum haloperidol levels and their relation to clinical response and adverse effects in 19 psychotic patients with positive symptoms treated with haloperidol. Methods: Blood samples were taken on Days 7, 14 and 21. Clinical evaluation was based on the PANSS, and UKU scales. The D2 antidopaminergic RRA was used to measure haloperidol serum levels. Results: Our results show a correlation between psychosis with positive symptoms assessed by positive scores in the PANSS and the serum drug level measured by RRA concentrations. The observed relationship made it possible to establish a therapeutic serum range of haloperidol equivalents 15–30 ng/ml⁻¹. This range contained no “non-responders”. Analysis of the correlation between each item on the positive subscale of the PANSS and the RRA concentration suggested that there was no specific symptom of psychosis closely related to RRA concentration during the first 15 days of treatment. In the third week, however, certain specific symptoms were closely connected to the RRA concentration. Conclusion: From these results, it can be concluded that antipsychotic activity can be related to blockade of serum D2 dopamine receptors. In future would be desirable to monitor neuroleptic treatment in this way. The study also showed that the antipsychotic treatment did not correct any specific component of the psychosis during the first stage of the treatment but that it did so at later times. Received: 19 May 1995/Accepted in revised form: 5 February 1996