Prolactin levels in male schizophrenic patients treated with risperidone and haloperidol: a double-blind and randomized study

Rationale There are few data from systematic, double-blind clinical trials that have compared the effect of the typical and the atypical antipsychotics on serum prolactin (PRL) levels in patients with schizophrenia.Objectives The goal of this study was to compare the effect of risperidone and haloperidol on serum PRL and investigate the relationship between serum PRL levels and clinical response in patients with schizophrenia.Methods Seventy-eight inpatients with a diagnosis of schizophrenia (according to DSM-III-R) were randomly assigned to 12 weeks of treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol after a 2-week washout period, using a randomized, double-blind design. Clinical efficacy was determined using the positive and negative syndrome scale (PANSS). Their serum PRL was assayed by means of radioimmunometric assay (RIA) between pre-treatment and post-treatment, and compared with 30 sex-matched and age-matched normal subjects.Results Both risperidone and haloperidol treatment significantly increased serum PRL levels in drug-free chronic schizophrenia patients (both P<0.001). Hyperprolactinemia induced by risperidone 6 mg/kg was comparable to levels produced by haloperidol 20 mg/day. Considering dose-adjusted serum PRL levels, risperidone treatment induced a significant elevation of PRL levels compared with haloperidol treatment at the haloperidol equivalent (P<0.001). Change in PRL levels at pre-treatment and post-treatment were related to positive symptom improvement seen in the risperidone group (r=0.51, P=0.016), but not in the haloperidol group (P>0.05). Female patients showed both a higher baseline and post-treatment PRL level and a greater increase in PRL than men (all P<0.05).Conclusions Risperidone is associated with a robust effect on prolactin secretion in contrast to the conventional antipsychotic haloperidol. Prolactin monitoring during risperidone treatment should be performed.     

High dosage haloperidol therapy in chronic schizophrenic patients: A double-blind study of clinical response,side effects,serum haloperidol,and serum prolactin

In a 12-weeks double-blind study high dosage versus standard dosage haloperidol therapy was evaluated in 23 male, chronic schizophrenic inpatients. The patients were relatively treatment-resistant and, in spite of traditional neuroleptic medication, were characterized by a moderate to severe degree of illness. At the end of the trial the dose of haloperidol in the standard dosage group was 12–36 mg/day (mean 15), in the high dosage group 10–240 mg/day (mean 103). No significant difference in therapeutic effect was found between the two groups as measured by the Brief Psychiatric Rating Scale and global assessment. About half the patients in both groups improved during the trial. A greater incidence of side effects was noticed in the high dosage group than in the standard group, especially in the form of sedation (5 of 12 patients), aggressive episodes (three patients), muscular weakness and tendency to fall (two patients), and epileptic attacks (one patient). The incidence of extrapyramidal phenomena showed fewer differences between the two groups. In addition, the high dosage group showed a temporary rise in serum alkaline phosphatase and serum aspartate-aminotransferase. There was a positive correlation between the dose of haloperidol and serum haloperidol, and between the haloperidol dose of up to 80 mg/day and serum prolactin. At higher doses prolactin response leveled off. Neither serum haloperidol nor serum prolactin showed any correlation to clinical response. It is concluded (1) that very high doses of haloperidol in only a few cases show any therapeutic advantage over haloperidol in standard doses; (2) that high dosage treatment has a higher incidence of side effects; and (3) that the serum concentrations of a given neuroleptic and of prolactin are of very limited value in the monitoring of neuroleptic treatment.     

Prolactin response to sodium valproate in schizophrenics with and without tardive dyskinesia

Sodium valproate, a GABAergic agent (800 mg), and placebo were administered orally, as a single dose, to nine chronic schizophrenics with tardive dyskinesia (TD), seven chronic schizophrenics without TD and ten healthy controls, according to a double blind design. Blood samples were collected before and after drug administration, to determine plasma prolactin concentrations. Sodium valproate decreased plasma prolactin levels in healthy subjects (P<0.001) and in schizophrenic patients with TD (P<0.001), but not in chronic schizophrenics without TD. Moreover, in dyskinetic subjects, the maximum per cent decrease of plasma prolactin from basal value was positively correlated to the score of the abnormal involuntary movement scale (r=0.724, P<0.02). Although the neural or biochemical substrate underlying the different responses of plasma prolactin to sodium valproate in schizophrenics with and without TD remains unclear, these results provide the first neuroendocrine evidence able to differentiate dyskinetic subjects from those without TD within a schizophrenic population.     

Tardive dyskinesia during and following treatment with haloperidol,haloperidol + biperiden,thioridazine, and clozapine

In a cross-over trial 16 elderly psychiatric patients with tardive dyskinesia were treated with thioridazine (median dose, 267.5 mg/day) for three months, followed by haloperidol (5.25 mg/day), haloperidol (5.25 mg/day) + biperiden (6 mg/day), thioridazine (267.5 mg/day), and clozapine (62.5 mg/day, only 7 patients), all for periods of 4 weeks with 4-week drug-free intervals. The tardive dyskinesia syndrome and the parkinsonism were evaluated blind according to a self-constructed rating scale and a modified Webster scale from weekly video-tape recordings. At the end of the treatment periods the hyperkinesia score was lower during haloperidol than during either thioridazine for 3 months (total score, 2.2 vs. 3.2, P<0.05), thioridazine for 4 weeks (total score, 2.2 vs. 4.8, P<0.02), or haloperidol + biperiden (score, 2.2 vs. 6.2, P<0.01). Clozapine had no significant antihyperkinetic effect, but in one patient it exerted a clear antiparkinsonian effect. After withdrawal of the initial thioridazine treatment, the hyperkinesia score was lower than after the subsequent haloperidol treatment (6.5 vs. 9.0, P<0.01), but after the second thioridazine period the hyperkinesia was of the same magnitude as after the preceding haloperidol periods. Biperiden increased the tardive dyskinesia syndrome during treatment, but did not significantly influence the syndrome after withdrawal of the treatment.It is concluded that (1) haloperidol (a strong antidopaminergic neuroleptic) has a more pronounced antihyperkinetic effect than thioridazine and clozapine (weaker antidopaminergic neuroleptics); (2) haloperidol might have a greater tendency to induce tardive dyskinesia than thioridazine; (3) administration of anticholinergics concomitant with neuroleptic drugs antagonizes the antihyperkinetic effect of haloperidol, but may not influence the intensity of tardive dyskinesia after withdrawal of the treatment.     

Perphenazine decanoate andcis(z)-flupentixol decanoate in maintenance treatment of schizophrenic outpatients

Two groups of schizophrenic outpatients were treated with perphenazine decanoate (N=20) andcis(z)-flupentixol decanoate (N=24) respectively. Every 3 months the dose was gradually reduced until symptoms appeared that were suggestive of a prodromal phase of a psychotic episode. A slightly higher dose was then promptly reinstituted (the minimum effective dose). At each dose level, two blood samples were drawn for determination of serum concentration. The mean minimum effective dose of perphenazine decanoate was 99.3 mg/2 weeks (range 21.6–270.5), while the mean minimum effective dose ofcis(z)-flupentixol decanoate was 60 mg/2 weeks (range 20–250). The corresponding mean serum level of perphenazine decanoate was 7.3 nmol/l (range 2.0–18.1) and ofcis(z)-flupentixol decanoate 7.8 nmol/l (range 1.2–37.0). There was a significant correlation between the administered doses and the corresponding serum levels for both drugs (r=0.87,P<0.01). A weak positive correlation was found between serum levels at the minimum effective dose and symptom intensity (BPRS total score) (r=0.53,P<0.02) for perphenazine, but notcis(z)-flupentixol. No correlation was found between serum levels and side effects or length of neuroleptic treatment. It is concluded that the serum drug concentrations corresponding to the lowest effective dose are so variable that routine serum level monitoring may be of limited value in the long-term maintenance treatment of schizophrenia.     

Relationship of serum prolactin with severity of drug use and treatment outcome in cocaine dependence

Rationale Alteration in serum prolactin (PRL) levels may reflect changes in central dopamine activity, which modulates the behavioral effects of cocaine. Therefore, serum PRL may have a potential role as a biological marker of drug severity and treatment outcome in cocaine dependence.Objective We investigated whether serum PRL levels differed between cocaine-dependent (CD) subjects and controls, and whether PRL levels were associated with severity of drug use and treatment outcome in CD subjects.Methods Basal PRL concentrations were assayed in 141 African–American (AA) CD patients attending an outpatient treatment program and 60 AA controls. Severity of drug use was assessed using the Addiction Severity Index (ASI). Measures of abstinence and retention during 12 weeks of treatment and at 6-month follow-up were employed as outcome variables.Results The basal PRL (ng/ml) in CD patients (9.28±4.13) was significantly higher than controls (7.33±2.94) (t=3.77, P<0.01). At baseline, PRL was positively correlated with ASI-drug (r=0.38, P<0.01), ASI-alcohol (r=0.19, P<0.05), and ASI-psychological (r=0.25, P<0.01) composite scores, and with the quantity of cocaine use (r=0.18, P<0.05). However, PRL levels were not significantly associated with number of negative urine screens, days in treatment, number of sessions attended, dropout rate or changes in ASI scores during treatment and at follow-up. Also, basal PRL did not significantly contribute toward the variance in predicting any of the outcome measures.Conclusion Although cocaine use seems to influence PRL levels, it does not appear that PRL is a predictor of treatment outcome in cocaine dependence.     

Gonadal axis hormones in male schizophrenic patients during treatment with haloperidol and after switch to risperidone

Rationale: The atypical neuroleptic risperidone, in addition to its dopamine receptor blocking activity, has a high affinity for serotonergic receptors. Since both dopaminergic and serotonergic neuronal activities participate in regulation of the pituitary – gonadal axis (PGA), it is expected that a switch from treatment with haloperidol to treatment with risperidone should influence plasma levels of PGA hormones. Objective: To study the effects of a drug with dopamine and serotonin receptor blocking activity on PGA hormones in patients who were on treatment with a dopamine receptor blocker. Methods: Plasma levels of testosterone, luteinizing harmone (LH) and follicle stimulating harmone (FSH), as well as prolactin and cortisol, were measured in 16 male schizophrenic patients during treatment with haloperidol (mean dose 23.3 mg daily, SD = 16.9) and 6 weeks later after switching to treatment with risperidone (mean dose 11.8 mg daily, SD = 2.9). Psychopathology was assessed by BPRS. Results: After switching to risperidone, total BPRS score and the scores in its subscales for positive, negative, and general symptoms were all significantly reduced in the order of 35–45%. Prolactin levels were significantly increased from 39.5 ± 22.3 to 58.9 ± 28.5 ng/ml (F = 4.61, P = 0.04), while cortisol, testosterone, LH, and FSH remained unchanged. No significant correlations between prolactin increases and reduction in BPRS or in its subscale scores were found. Conclusions: The results show that blocking of both dopamine and serotonin receptors does not influence the pituitary – gonadal axis but considerably increases prolactin release. Received: 29 June 1998/Final version: 23 October 1998     

Serum neuroleptic activity,prolactin, and tardive dyskinesia in schizophrenic outpatients

The authors measured serum neuroleptic activity and serum prolactin levels in 26 schizophrenic outpatients on prolonged neuroleptic therapy. Of the 24 patients, 11 had moderafe to severe tardive dyskinesia, as assessed by the Abnormal Involuntary Movement Scale (AIMS). AIMS scores were positively correlated with age, duration of illness, and negative schizophrenic symptoms, but not with variables of neuroleptic exposure, current serum levels of neuroleptic activity, or serum prolactin levels. Neuroleptic activity and prolactin levels were positively correlated, and both variables also correlated with the current daily dose of neuroleptics.     

A placebo-controlled trial of fluoxetine added to neuroleptic in patients with schizophrenia

Following a 2-week placebo lead-in, schizophrenic patients were randomly assigned to fluoxetine 20 mg/day or placebo added to depot neuroleptic for a 6-week, double blind trial. All patients had received a stable dose of depot neuroleptic for at least 6 months and did not meet criteria for depression. Serum samples were obtained at baseline and at weeks 4 and 6. Scores on the negative symptom subscale of the Brief Psychiatric Rating Scale (BPRS) were significantly lower at week 6, controlling for baseline scores, in patients receiving fluoxetine (n=20) compared to patients receiving placebo (n=21). Measures of psychosis, depression, global functioning and extrapyramidal symptoms (EPS) did not differ between groups at week 6. Fluoxetine administration was associated with a mean 65% increase in serum fluphenazine concentrations in 15 patients and a mean 20% increase in serum haloperidol concentrations in three patients. The change in negative symptoms at week 6 did not correlate with serum concentrations of fluoxetine or norfluoxetine, but did inversely correlate withS-norfluoxetine, an active stereoisomer of fluoxetine. For these chronically ill patients, fluoxetine significantly improved negative symptoms and did not worsen EPS, despite causing substantial elevation in serum concentrations of neuroleptics.     

Clozapine serum levels and side effects during steady state treatment of schizophrenic patients: a cross-sectional study

Serum clozapine (S-Cloza) and serum desmethyl-clozapine concentrations (S-Descloza) were measured in 30 chronic schizophrenic in- and outpatients on a variable dose regimen. All patients were in steady state with respect to clozapine therapy and in a stable condition with respect to psychotic illness. The 24-h clozapine dose (median with interquartile range in parenthesis) was 350 (228–425) mg/24 h (range 100–700). There was a weak positive correlation between doses and the BPRS total score (r=0.44,P<0.05). The median S-Cloza was 1076 (706–1882) nmol/l (range 196–5581 corresponding to 64–1824 ng/ml). The S-Cloza was linearly correlated to dose but with a high interindividual variation at equal doses, e.g. a factor of 8 at 400 mg/24 h, but a low intraindividual variability of 20%. The S-Descloza averaged 77% of the S-Cloza and was highly correlated to S-Cloza (r=0.90;P<0.001). The S-Descloza/dose ratio increased with age and duration of treatment. The side effects registered were EEG abnormalities (83%), tachycardia (23%), increased liver enzyme activity (60%), orthostatic hypotension (17%), and moderate leucocytosis (17%). Only EEG changes were correlated to S-Cloza (r=0.43;P<0.05). The score values of the UKU Side Effect Scale were weakly (r=0.36) correlated to S-Cloza. No side effects were correlated to S-Descloza, doses, or treatment duration. The frequency of side effects was higher than in studies using lower mean doses indicating a correlation between doses or S-Cloza and the frequency of side effects. It is concluded that clozapine fulfils the criteria for therapeutic drug monitoring. TDM may contribute to finding the lowest effective dose with the fewest possible side effects.     

Sertindole and dopamine D2 receptor occupancy in comparison to risperidone, clozapine and haloperidol – a 123I-IBZM SPECT study

The striatal D₂ dopamine binding was studied in schizophrenic patients treated with the novel atypical antipsychotic drug sertindole (n = 10). Comparisons were obtained with haloperidol (n = 8), clozapine (n = 6), risperidone (n = 11) and untreated healthy controls (n = 8) of a dataset which has partly been reported previously. ¹²³I-Iodobenzamide (IBZM) single photon emission computerized tomography (SPECT) was used for estimation of striatal dopamine D₂ receptor binding. Sertindole-treated patients exhibited significantly (P < 0.001) lower levels of striatal D₂ binding (BG/FC ratio:1.28) compared with those treated with haloperidol (BG/FC ratio:1.09) and risperidone (8 mg:1.18) but significantly (P < 0.005) higher levels compared with clozapine (BG/FC ratio:1.49). However, if patients were pretreated with a depot neuroleptic, significantly (P < 0.05) higher striatal D₂ binding (BG/FC ratio:1.12) has been obtained. Since sertindole has been shown to exert distinct clinical efficacy for treatment of positive and negative symptoms, our data are indicative that antipsychotic efficacy is not associated with a high degree of striatal D₂ receptor occupancy in schizophrenic patients. Received: 21 July 1997/Final version: 27 October 1997     

Plasma concentration of neuroleptic and serum prolactin in patients chronically receiving depot fluphenazine: No evidence of tolerance

The authors determined neuroleptic dose, plasma level of drug, and serum prolactin in 76 outpatients receiving depot fluphenazine. The patients had received neuroleptic treatment for periods ranging from 3 to 23 years (median 13 years). Plasma level of drug correlated with dose (r_s = 0·73, p>0·0001). Prolactin levels were linearly correlated with dose (r_s = 0·42, p = 0·0001) and plasma level of drug (r_s = 0·64, p>0·0001). There was a tendency for dose and, concomitantly, plasma level of drug, to decrease with age (r_s = ?0·29, p = 0·01, for each). However, dose, plasma level of drug adjusted for dose, and serum prolactin adjusted for plasma level of drug did not correlate with duration of treatment. Neither did any of these measures correlate with treatment duration when adjusted for age. The findings suggest that while older patients were given lower doses of medication, changes in the metabolism of fluphenazine or tolerance to its prolactin-elevating effects did not occur during extended treatment.     

Induction of microsomal enzyme activity by flupenthixol in chronic schizophrenics

The effect of long-term treatment with flupenthixol on hepatic microsomal enzyme activity was studied in 12 chronic schizophrenic outpatients who had been receiving two weekly maintenance doses for at least 6 months. Antipyrine half-life was measured in the 12 patients while they continued to receive the drug. Flupenthixol was then discontinued for 6 weeks and antipyrine half-life was repeated in 7 of the 12 patients. In the 12 patients the plasma antipyrine elimination half-life was 4–24 h (mean 9.73±1.61 h) when receiving flupenthixol and there was a significant negative correlation between antipyrine half-life and the dose of flupenthixol (r=0.582, P<0.05). In the seven patients to whom antipyrine was given on two occasions, antipyrine half-life was 7.33±1.07 h and 12.04±1.87 h on and off flupenthixol treatment respectively. The clearance significantly decreased when flupenthixol was discontinued, but there was no change in the apparent volume of distribution.     

An early Phase II clinical trial of BW234U in the treatment of acute schizophrenia in newly admitted patients

Sixteen schizophrenic patients, who were newly admitted to hospital from the emergency room, underwent a 3–6-day washout before being treated for 4 weeks with BW234U, a dimethylpiperazinyl-propylcarbazole derivative. Eight patients showed moderate to marked improvement in schizophrenic symptoms and there was a statistically significant (P<0.001) reduction in the mean score for Clinical Global Impressions in all patients. Four patients did not complete the trial; two because of poor therapeutic effect, one because of a grand-mal seizure and one because of an episode of loss of consciousness of unknown origin. BW234U showed no evidence of neuroleptic plasma activity (as measured by radioreceptor assay), did not induce plasma prolactin elevation and did not appear to cause parkinsonism.     

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.     

Striatal dopamine D2 receptor density in neuroleptic-naive and in neuroleptic-free schizophrenic patients: an 123I-IBZM-SPECT study

Most post-mortem autoradiographic studies have described striatal dopamine D₂ receptor up-regulation due to chronic neuroleptic exposure. The aim of our study was to compare in-vivo striatal D₂ receptor density in neuroleptic-naive and neuroleptic-free schizophrenic patients. We included 28 young (mean age: 28±8 years) acute psychotic patients meeting DSM-IV criteria for schizophrenia or schizophreniform disorder. Enrolled patients were either first-episode neuroleptic-naive (n=12) or neuroleptic-free (n=16) after a minimum washout period of 7 days. All neuroleptic-free subjects had previously received neuroleptic treatment for a median period of 3.5 years. Both groups were evaluated using standard clinical scales. In-vivo striatal D₂ receptor binding was assessed by basal ganglia/frontal cortex ratios using ¹²³I-IBZM SPECT. No statistically significant differences were found in age or clinical assessment between neuroleptic-naive and neuroleptic-free schizophrenic patients. No differences were found in the basal ganglia/frontal cortex ratios of neuroleptic-naive (1.78±0.11) and neuroleptic-free (1.81±0.15) patients. No striatal uptake laterality was observed in either group. No correlation was demonstrated between BG/FC ratios and duration of illness, period of neuroleptic exposure or time of drug washout. We conclude that our neuroleptic-naive and neuroleptic-free schizophrenic patients did not show differences in striatal D₂ receptor binding, suggesting that IBZM-SPECT fails to detect D₂ receptor up-regulation induced by chronic exposure to neuroleptic drugs.     

Relationship between prolactin response and antipsychotic effect of thioridazine in psychiatric patients

Summary Neuroleptic drugs may exert their antipsychotic effect by interference with central dopaminergic mechanisms. Tuberoinfundibular dopaminergic neurons may also be affected, which will increase prolactin secretion from the pituitary. Accordingly, a study has been made in 23 patients with acute paranoid psychosis, treated with thioridazine, of repeated ratings of psychiatric symptoms (CPRS) and of serum prolactin concentration. There was a close correlation between the serum concentration of prolactin and low doses of thioridazine, but at higher doses the increase in prolactin level gradually levelled off. At a given dose the prolactin response to thioridazine showed large interindividual variation and female patients had higher serum prolactin concentrations than males. The prolactin response to thioridazine was unaffected by time of treatment, age or body weight. In individual patients a correlation was found between serum prolactin level and amelioration of psychiatric symptoms, as reflected by the psychiatric rating score (p<0.001). After normalization of the data, the same relationship was also found for the entire group of patients. The dose-response relationship of prolactin to thioridazine showed saturation kinetics and linear transformation by a Woolfe-plot was done. Therefore, it appears possible to predict the thioridazine dose that would give the maximal prolactin response (and maximal clinical effect) and thereby optimize the regimen of antipsychotic medication in the individual patient.     

Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance

Plasma concentrations of haloperidol and its reduced metabolite (reduced haloperidol) were investigated in cigarette smokers (N=23) and nonsmokers (N=27). Steady-state plasma concentrations were obtained 12 h post bedtime dose. Haloperidol and reduced haloperidol concentrations were determined by RIA. Reduced haloperidol was separated by selective succinylation and liquid chromatography. Patients were clinically assessed with the Clinical Global Impression Scale (CGIS). Smokers had significantly lower haloperidol and reduced haloperidol plasma concentrations than nonsmokers (P<0.01, P<0.05). Clearance of haloperidol was significantly greater in smokers compared to nonsmokers (P=0.0052). CGIS assessments did not show significant differences between smokers and non-smokers. Plasma concentrations should be carefully monitored when patients either start or stop smoking.Presented at the IV World Congress of Biological Psychiatry, Philadelphia, PA, September 8–13, 1985     

Acute extrapyramidal side effects: Serum levels of neuroleptics and anticholinergics

An assay technique for measuring anticholinergic drugs in human serum based upon their inhibition of the specific binding of [³H]-quinuclidinyl benzilate to rat brain muscarinic receptors is described. The assay was validated by demonstrating a close correlation (r=0.99) between serum levels of nortriptyline measured by the radioenzymatic assay and a GLC technique. The assay measures free anticholinergics, and under standard assay conditions, approximately 95% of benztropine is bound to serum protein. Marked variation in serum anticholinergic levels in patients receiving the same oral dose was observed, and in individual patients there was a non-linear relationship between increasing oral dose and serum anticholinergic levels.In a cross-sectional study of 109 patients receiving concurrently neuroleptics and antichlinergics, there was no correlation (r=0.029) between serum neuroleptic levels measured by a radioreceptor assay and extrapyramidal side effects (EPS). In the patients whose serum anticholinergic levels were also determined, there was a significant inverse correlation (r=0.44) between anticholinergic levels and EPS. In this cohort of patients, there was no significant correlation between serum anticholinergic and serum neuroleptic levels (r=0.16) and the ratio of serum anticholinergic to serum neuroleptic was a poor predictor of EPS (r=0.26).The results suggest a marked variation in sensitivity of patients to the EPS-inducing of neuroleptics; nevertheless, the incidence of EPS decreases with increasing serum levels of anticholinergics. An optimal serum anticholinergic level of 10 pmole atropine equivalent per ml was associated with a low incidence of EPS and is relevant to drug action at the striatal muscarinic receptor.     

A fixed dose study of the plasma concentration and clinical effects of thioridazine and its major metabolites

Fifty-three patients in an acute episode or exacerbation of psychosis were given thioridazine 200 or 400 mg daily for 2 weeks. Thioridazine and its active metabolites, mesoridazine and sulforidazine, were estimated in plasma by high performance liquid chromatography (HPLC) and radioreceptor assay (RRA). One week after institution of treatment, plasma concentrations of drug were stable in the morning 12 h after dosing. Drug levels varied widely between patients, but in all patients the relative level of thioridazine to mesoridazine was about one half and thioridazine to sulforidazine was about two fold. Estimates of neuroleptic activity by RRA and the weighted sum of thioridazine, mesoridazine and sulforidazine by HPLC were very similar. Plasma concentration of parent compound, metabolites, or the sum of active substances as estimated by HPLC or RRA, showed only modest correlations (r _s=0.10–0.22, all NS) to the degree of improvement as measured by change on the Brief Psychiatric Rating Scale. Significant correlations were observed between plasma concentrations of drug and side effects, including dry mouth, blurred vision, or total rating on the Somatic Symptoms Scale. Even patients receiving the lowest dose and achieving the lowest plasma concentrations of drug showed considerable improvement. There was suggestive evidence that the patients achieving the highest plasma levels of drug did not have the best clinical outcome. These and similar observations from other studies suggest that currently used doses of neuroleptics may be excessive. Optimal drug effects as well as stronger relationships between dose, drug concentration, and clinical therapeutic effects might best be sought at doses below those in common use.