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.     

Pharmacokinetic protocol for predicting plasma haloperidol concentrations

The accurate prediction of steady-state plasma haloperidol concentrations was successfully accomplished by obtaining two blood samples following a 20 mg test dose (kinetic method). Prediction of steady-state concentrations on the basis of a mg/kg/day dosage (dose method), although equally precise, generated significantly less information concerning the variance between observed and predicted haloperidol plasma concentrations. Both predictive methods were less precise when the daily doses exceeded 0.47 mg/kg/day. Fifty percent (6/12 patients) of the haloperidol plasma concentrations were underpredicted if this threshold was exceeded. This finding may suggest the possibility of dose-dependent pharmacokinetics with haloperidol in some patients.     

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.     

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.     

Determining the optimal dose of haloperidol in first-episode psychosis.

Uncertainty exists as to the most appropriate dose of haloperidol in first-episode psychosis. This study set out to determine whether ultra-low doses of haloperidol could successfully treat patients with first-episode psychosis. Thirty-five patients with a first episode of psychosis were treated with haloperidol in an open label, fixed protocol over a 12-week period with doses restricted to 1 mg per day for the first 4 weeks. Twenty-nine (83%) remained on haloperidol after 12 weeks at a mean dose of 1.78 mg per day, 16 (55%) had stabilized on 1 mg/day or less. The mean percentage reduction in Positive and Negative Symptom Scale score between baseline and 6 and 12 weeks was 30.3% (SD 20.9%) and 41.4% (SD 16.6%), respectively. There were no significant differences in mean extrapyramidal symptom ratings between baseline and 12 weeks. Ultra-low doses of haloperidol are effective and well tolerated in first-episode psychosis. Initial doses should be maintained for a sufficient period of time to allow for the medication to take full effect.     

Levels of insulin in the brains of rats modified by chronic administration of amphetamine, haloperidol and sulpiride

Rats treated with two classic neuroleptic drugs at therapeutic doses, haloperidol (0.05 mg/kg/day i.p.) and sulpiride (3 mg/kg/day i.p.) showed a marked decline in cerebral levels of insulin (0.085 +/- 0.02 ng/g and 0.120 +/- 0.04 ng/g wet weight respectively) compared to the control group (0.383 +/- 0.05 ng/g wet weight), while rats given D-amphetamine bitartrate chronically (20 mg/kg/day p.o.) showed an increase in cerebral insulin (0.55 +/- 0.04 ng/g wet weight). Combining treatment with each neuroleptic drug and amphetamine, at the same doses, produced a significant decrease in cerebral levels of insulin (P less than 0.001) as in the amphetamine animals. In the groups of rats treated with haloperidol, sulpiride and both of these drugs combined with amphetamine, there was a slight increase in levels of serum insulin, more so in the neuroleptic groups. Serum glucose values did not vary.     

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.     

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.     

Context-dependent cocaine sensitization: differential effect of haloperidol on development versus expression

Repeated, intermittent administration of psychomotor stimulants has been shown to produce increasing effects (behavioral sensitization) in many species of animals. In a novel two-day sensitization paradigm, rats that received a single high dose of cocaine (40 mg/kg) compared with saline on day 1 showed an increased locomotor response to a challenge dose (10 mg/kg) on day 2. This effect is conditioned or context-dependent; i.e., it is only observed if the rats received cocaine in an environment similar to the test environment. If the cocaine-induced hyperactivity on day 1 is prevented with pharmacological agents such as haloperidol and diazepam, sensitization on day 2 does not occur. Furthermore, although moderate (0.2 mg/kg) and high doses (0.5 mg/kg) of haloperidol (day 1) prevented the development of sensitization to cocaine, they were ineffective when given prior to the day 2 challenge dose in preventing the expression of sensitization. Thus, this type of cocaine sensitization appears to involve conditioning, show stimulus generalization, and offer a possible model for clinical neuroleptic nonresponsiveness once stimulant-induced pathological behavior has been induced.     

Chronic treatment with clozapine, unlike haloperidol, does not induce changes in striatal D-2 receptor function in the rat

Comparison has been made of the effects on brain dopamine function of chronic administration of haloperidol or clozapine to rats for up to 12 months. In rats treated for 1-12 months with haloperidol (1.4-1.6 mg/kg/day), purposeless chewing jaw movements emerged. These movements were only observed after 12 months' treatment with clozapine (24-27 mg/kg/day). Apomorphine-induced (0.125-0.25 mg/kg) stereotyped behaviour was inhibited during 12 months treatment with haloperidol. Clozapine treatment was without effect. After 12 months, stereotypy induced by higher doses of apomorphine (0.5-1.0 mg/kg) was enhanced in haloperidol, but not clozapine, treated rats. Bmax for striatal 3H-spiperone binding was elevated throughout 12 months of haloperidol administration, but was not altered by clozapine treatment. Bmax for striatal 3H-NPA binding was only elevated after 12 months of haloperidol treatment; clozapine treatment was without effect. Bmax for 3H-piflutixol binding was not altered by haloperidol treatment, but was increased after 9 and 12 months of clozapine treatment. Dopamine (50 microM)-stimulated adenylate cyclase activity was inhibited after 1 month's haloperidol treatment but normal thereafter. Adenylate cyclase activity was not altered by chronic clozapine treatment. Striatal acetylcholine content was increased after 3 and 12 months of haloperidol or clozapine intake. These findings indicate that the chronic administration of the atypical neuroleptic clozapine does not produce changes in brain dopamine function which mirror those of the typical neuroleptic haloperidol. In particular, chronic administration of clozapine, unlike haloperidol, does not appear to induce striatal D-2 receptor supersensitivity. Unexpectedly, clozapine treatment, unlike haloperidol, altered D-1 receptor function.     

Total and free serum haloperidol levels in schizophrenic patients and the effect of age thioridazine and fatty acid on haloperidol-serum protein binding in vitro.

1 Using radioimmunoassays, steady-state levels of total and free haloperidol (obtained by ultrafiltration and dialysis) have been determined in twenty-two patients on long term treatment receiving doses from 3 to 45 mg per day. 2 For the group, both total serum concentration and free drug concentration showed significant correlations (P less than 0.001) with daily dose. 3 No significant correlation was observed between age of the patient and percentage free haloperidol in serum. 4 In vitro experiments using sera from twenty-three healthy volunteers showed significant negative correlations (P less than 0.01) between age and percentage free haloperidol. 5 Thioridazine and oleic acid significantly enhanced the percentage of free haloperidol in normal human sera in vitro.     

Behavioral effects of sertindole,risperidone, clozapine and haloperidol inCebus monkeys

Extrapyramidal side effects (EPS) are major limitations to neuroleptic treatment of psychoses. To evaluate further the behavioral characteristics of the novel antipsychotic agents, a wide range of single intramuscular doses of sertindole (0.1–2.5 mg/kg IM), risperidone (0.01–0.25 mg/kg IM), clozapine (1.0–25.0 mg/kg IM), and haloperidol (0.01–0.25 mg/kg IM) were blindly evaluated at weekly intervals inCebus monkeys previously sensitized to neuroleptics. All drugs except clozapine produced dystonia and parkinsonian symptoms, but haloperidol and risperidone were 50–100 times more potent than sertindole in producing EPS. Sertindole, risperidone and haloperidol had no significant sedative effects, whereas clozapine produced dose related sedation. Risperidone, clozapine and haloperidol but not sertindole decreased locomotor activity. Sertindole, risperidone and clozapine had a calming effect at doses below the EPS threshold, unlike haloperidol. Sertindole has many behavioral effects in nonhuman primates that are similar to those seen with the new antipsychotics, risperidone and clozapine, which suggests a favorable antipsychotic benefit/risk ratio in the clinic, especially regarding EPS.     

Conditioned taste aversion to chlorpromazine,but not to haloperidol

Using in rats a Conditioned Taste Aversion (CTA) procedure, chlorpromazine was shown to possess significant US properties at the highest dose tested (8 mg/kg IP repeated four times). In contrast, haloperidol failed to exert a similar effect at a dosage (1.6 mg/kg IP X 4) at least twice as high, in terms of pharmacological activity, as the effective chlorpromazine dosage. These data suggest that the induction of neuroleptic extrapyramidal side effects and the antidopaminergic properties shared by the two drugs may not be responsible for the aversive effect of chlorpromazine. However, it cannot be excluded than haloperidol produces an aversion which is antagonized by some action of the drug not shared by chlorpromazine.     

Olanzapine for injection: new formulation. No advantage in agitated patients

(1) The intramuscular neuroleptic of choice for the treatment of agitated schizophrenic patients and patients with acute mania is haloperidol, at a dose of 5 mg. Olanzapine is now marketed in France for hospital use in both these indications. (2) In two comparative trials in patients with schizophrenia, olanzapine 10 mg was shown to be no better than haloperidol 7.5 mg (a high dose). Control of agitation was satisfactory in three-quarters of patients after a single injection of either neuroleptic. (3) Olanzapine has not been compared with other neuroleptics in the treatment of acute mania. In one trial, olanzapine acted faster than lorazepam for injection (used at a rather low dose). (4) In one trial, patients given olanzapine had a lower incidence of acute dystonia and extrapyramidal symptoms (about 1%) than patients given haloperidol (about 6-7%), but the haloperidol dose (7.5 mg) was higher than recommended in the SPC (5 mg). The incidence of postural hypotension was significantly higher among patients given olanzapine (about 12%) compared with haloperidol (about 3%). (5) In practice, haloperidol remains the intramuscular neuroleptic of choice for the treatment of agitated patients with schizophrenia or acute mania.     

Neuroleptic-induced vacuous chewing movements in rodents: incidence and effects of long-term increases in haloperidol dose

Rats treated chronically with neuroleptics develop vacuous chewing movements (VCMs), similar in some respects to tardive dyskinesia (TD) in man. The VCM syndrome was used as a model of TD to examine the ability of increased neuroleptic doses to produce long-term suppression of dyskinetic movements. The incidence and persistence of the VCM syndrome in individual rats were also assessed to look for affected and unaffected subgroups. Rats were initially treated for 15 weeks with haloperidol decanoate. For the next 21 weeks, half the group received a 50–150% increase in dose while the other half continued to receive the same dose. Animals were also followed during a 28-week withdrawal period. Total VCM ratings showed a skewed distribution, with some rats exhibiting few movements while others developed marked and persistent movements. Increasing doses did not suppress VCMs, nor did they exacerbate movements during the withdrawal period. To the extent that the VCM syndrome models TD, the absence of long-term suppression of the VCM syndrome suggests that, at this dosage range, increasing depot neuroleptic doses may not be a useful long-term strategy for TD suppression.     

Acute mania: haloperidol dose and augmentation with lithium or lorazepam

Antipsychotic dosing for acute mania has not been well studied. Combined treatment with lithium and an antipsychotic is the most common treatment, but additional antimanic efficacy of a lithium-antipsychotic combination beyond that of an antipsychotic alone has not been well demonstrated. Furthermore, the possibility that lithium could affect antipsychotic dose requirement is believed to have never been studied. In this study, 63 acutely psychotic bipolar manic inpatients were randomly assigned to receive double-blind treatment with 1 of 2 haloperidol doses, 25 mg/day or 5 mg/day, for 21 days. In addition to haloperidol, subjects were randomly assigned to receive concomitant treatment with placebo, standard lithium, or lorazepam 4 mg/day. The high haloperidol dose produced greater improvement and more side effects than did the low dose. Lithium added to the low dose produced a markedly greater clinical response than did the low dose alone. Lorazepam did not improve the outcome for the patients receiving low-dose haloperidol. The clinical response produced by high-dose haloperidol was not enhanced by adding either lithium or lorazepam. All treatment effects emerged by the fourth day of treatment and persisted. Used alone, a haloperidol dose of 5 mg/day is too low for most manic patients, but concomitant lithium produces a dose-dependent enhancement of haloperidol response. Lorazepam 4 mg/day was insufficient to produce an advantage when added to low-dose haloperidol.     

Substantial rise in sparteine metabolic ratio during haloperidol treatment

A sparteine test was carried out in 14 patients suffering from acute schizophrenic psychoses before and 1-2 times during oral haloperidol treatment in doses of 10-40 mg day-1. In patients classified as extensive metabolisers (sparteine MR less than 20 before treatment), haloperidol treatment resulted in a rise in sparteine MR that correlated with the serum-haloperidol concentration both within and between patients. At the highest serum haloperidol concentrations (60-80 nM) an increase in sparteine MR by a factor 15-50 was seen, but no patients were transformed into phenotypically poor metabolisers. The steady state concentration of haloperidol on the initial standard dose of 10 mg day-1 was the same in one patient classified as a sparteine poor metaboliser (MR = 112) as in eleven patients classified as extensive metabolisers (MR:0.22-1.47).     

Low dose oral haloperidol and blood levels in Alzheimer's disease: a preliminary study.

Nineteen patients with probable Alzheimer's disease who manifested psychosis or behavioral disturbance received 0.5 to 5 mg per day of oral haloperidol, with blood levels drawn on a stable daily dose. Oral dose correlated strongly with haloperidol blood levels assessed by radioimmunoassay (r = 0.82, p = .0001). The stronger correlation observed between oral dose and blood level compared with most studies in schizophrenia may be related to the fact that virtually all the Alzheimer's patients were neuroleptic naive, without the alterations in absorption and metabolism known to occur in schizophrenics receiving long-term neuroleptic treatment. Compared with oral dose, blood levels showed stronger relations to changes in symptoms and to changes in severity of extrapyramidal side effects. These preliminary data suggest that the utility of monitoring haloperidol blood levels in patients with Alzheimer's disease merits further investigation.     

A comparison of the effects of quetiapine ('seroquel') and haloperidol in schizophrenic patients with a history of and a demonstrated, partial response to conventional antipsychotic treatment. PRIZE Study Group

Quetiapine ('Seroquel') is a well-tolerated, novel, atypical antipsychotic with consistent efficacy in the treatment of schizophrenia. To date, no clinical studies have evaluated the effect of quetiapine in patients who only partially respond to conventional antipsychotics, yet this type of patient is most frequently seen by psychiatrists. Therefore, this international, multicentre, double-blind study was conducted to compare the efficacy and tolerability of 8 weeks' treatment of quetiapine 600 mg/day with haloperidol 20 mg/day in 288 patients who had a history of partial response to conventional antipsychotics and displayed a partial or no response to 1 month of fluphenazine (20 mg/day) treatment. Patients on quetiapine tended to have greater improvement than those on haloperidol in the primary efficacy measure, mean Positive and Negative Symptom Scale (PANSS) score, after 4 weeks' treatment (-9.05, -5.82, respectively, P = 0.061) and at study end (-11.50, -8.87, respectively, P = 0.234). Similarly, there was a trend towards patients on quetiapine demonstrating greater improvements in the secondary efficacy measures (Clinical Global Impression, PANSS subscale and Brief Psychiatric Rating Scale scores) [week 4 (baseline) to week 12 (end)], but the difference between treatments did not reach significance. Significantly more patients on quetiapine than on haloperidol showed a clinical response-patient response rates, defined as > 20% reduction in PANSS total score between weeks 4 and 12, were 52.2% for quetiapine and 38.0% for haloperidol (P = 0.043). Patients receiving quetiapine required less anticholinergic medication (P < 0.011), had greater reduction in extrapyramidal symptoms (EPS) (P = 0.005) and fewer treatment-emergent EPS-related adverse events compared to those on haloperidol (P < 0.001). Serum prolactin concentrations were elevated at the end of fluphenazine treatment in 73% of patients. Between weeks 4 and 12, elevated serum prolactin concentrations significantly decreased in quetiapine-treated patients compared to those receiving haloperidol (P < 0.001). At the end of quetiapine treatment, 83% of patients had normal prolactin levels while only 21% of patients receiving haloperidol were within the normal range. These results suggest that quetiapine may make a valuable contribution to the management of patients with a history of partial response to conventional antipsychotics.     

Unusual interactions between the neuroleptic haloperidol, and the dopamine D2 partial agonist, terguride

Terguride is an ergoline derivative which has been reported to act as a partial agonist at central dopamine D2 receptors. Depending on the state of the receptor, terguride may resemble an agonist or an antagonist in its pharmacological effects. The present study investigated interactions of terguride with the dopamine D2 antagonist haloperidol in the rat. Terguride (0.025 mg/kg, i.p.) lowered, whereas haloperidol (0.025 mg/kg, s.c.) increased serum prolactin levels. When given together there was a tendency for prolactin to be lowered, i.e. terguride fully antagonized the action of haloperidol. Both terguride and haloperidol dose-dependently reduced locomotor activity, with terguride being at least 50 times more potent. However, in the presence of a subthreshold dose of haloperidol (0.1 mg/kg), terguride was effective in reducing locomotor activity. Terguride and haloperidol were equally potent in disrupting performance of lever pressing for food on a VI 120 sec schedule (ED(50) values 0.22 and 0.28 mg/kg, respectively). When given together, there was a statistically significant interaction; a terguride dose of 0.2 mg/kg lowered rates of lever pressing when given with vehicle or a low (0.03 mg/kg) haloperidol dose, but antagonized the effect of 0.3 mg/kg haloperidol. Terguride dose-dependently disrupted lever pressing for intracranial stimulation reward (ED(50) value approx. 0.3 mg/kg). Haloperidol (0.26 mg/kg) also disrupted lever pressing but the two drugs together showed no greater effect than haloperidol alone. These observations are discussed in the context of terguride's suggested partial agonistic properties.