Effects of intermittent and continuous haloperidol administration on the dopaminergic system in the rat brain

The after-effect of intermittent and of continuous treatment with haloperidol on the dopaminergic system of the rat brain was studied. Each rat was treated for 14 days with either a single daily intraperitoneal injection of haloperidol (intermittent haloperidol group) or with a subcutaneously implanted pump that released haloperidol for 14 days (continuous haloperidol group). The total amount of haloperidol administered was 28 mg/kg in each animal of both groups. On the seventh day after cessation of injections or removal of pumps, the changes in dopamine (DA) metabolism after a challenge dose of haloperidol (1 mg/kg, intraperitoneally) were noted, and the number of [3H]spiperone binding sites in the striatum were recorded. The continuous haloperidol group showed a greater tolerance response to the influence of haloperidol on stimulation of DA turnover and also showed a larger increase in the number of [3H]spiperone binding sites than the intermittent haloperidol group. It is concluded that continuously administered haloperidol exerts a stronger effect on DA transmission, which in turn produces a greater tolerance to an acute dose of haloperidol than intermittent haloperidol administration.     

Comparison of the risk of adverse events between risperidone and haloperidol in delirium patients

The aim of this study was to determine the risk of adverse events for risperidone and haloperidol in delirium patients. The authors conducted a retrospective study with medical records of 266 Japanese delirium inpatients who were referred to them between July 2001 and May 2005. Information on gender, age, delirium, drug therapy, adverse events, death, and other relevant factors was collected and analyzed for each patient. As a primary antipsychotic drug for the treatment of delirium, risperidone was used in 93 patients; oral haloperidol was used in 95; and intravenous or intramuscular haloperidol was used in 61. The incidence of adverse events was 6.5% for risperidone, 31.4% for oral haloperidol, and 32.8% for haloperidol injection. The incidence of death during delirium was 3.2% for risperidone, 2.1% for oral haloperidol, and 13.1% for haloperidol injection. The incidence of death within 1 year after the onset of delirium was 30.1% for risperidone, 29.5% for oral haloperidol, and 45.9% for haloperidol injection. Between risperidone, oral haloperidol, and intravenous or intramuscular haloperidol the incidence of adverse events was significantly lowest for risperidone, and the incidence of death during delirium was significantly highest for intravenous or intramuscular haloperidol. The use of haloperidol as a first-line drug in delirium patients who can receive the drug orally will not contribute to the establishment of drug therapy for delirium based on risk-benefit assessment of the therapy.     

Comparison of haloperidol and reduced haloperidol plasma levels in four different ethnic populations.

1. Plasma haloperidol and reduced haloperidol concentration were measured in four ethnic populations. 2. Plasma samples were obtained under steady-state conditions and obtained 10-12 hours post bedtime dose and prior to the morning dose. 3. Haloperidol and reduced haloperidol plasma levels were assayed by radioimmunoassay and liquid chromatography. 4. A wide interpatient variability between haloperidol dose and plasma concentration was observed for each ethnic group. 5. The Chinese group differed from the other ethnic populations. 6. A nonlinear relationship was observed between haloperidol and reduced haloperidol plasma levels in each ethnic group. Further, the relationship of haloperidol to reduced haloperidol plasma levels differed for each ethnic group. These results suggest that various ethnic groups could metabolize haloperidol and reduced haloperidol differently.     

Reduced haloperidol/haloperidol ratio and clinical outcome in schizophrenia: preliminary evidences

1. The possible influence of haloperidol and its metabolite plasma levels on clinical outcome in schizophrenic patients was evaluated. 2. 18 schizophrenic inpatients diagnosed according to DSM III, were treated with conventional haloperidol p.o. for four weeks. 3. Plasma levels of haloperidol and its reduced metabolite were measured by mass-spectrometry assay. Clinical outcome was evaluated by BPRS. 4. Cluster analysis only considering BPRS improvement and reduced haloperidol/haloperidol ratio was able to discriminate two groups of patients: one of non responders and the other of responders. The former group presented higher ratios than the latter. 5. Reduced haloperidol/haloperidol ratio could be considered as a good marker for prediction of the clinical outcome.     

Regional distribution and kinetics of haloperidol binding in human brain: a PET study with [18F]haloperidol.

The regional distribution and the kinetics of haloperidol uptake in human brain were examined using [18F]haloperidol and PET in 9 controls and 5 schizophrenics while on haloperidol medication and after haloperidol washout. The regional distribution of [18F]N-methylspiroperidol, a tracer for D2 receptors, was measured in 1 normal subject for comparison. The uptake of [18F]haloperidol in the whole brain in normals was high (6.6% of the injected dose at 2 hr), and regional distribution was much more extensive than could be accounted for by the distribution of dopamine D2 receptors. In normals, the cerebellum, basal ganglia, and thalamus showed a greater concentration than the cortex, and there was minimal clearance of 18F from the brain during the 10-hr period of the study. Medicated schizophrenics showed a total brain uptake of 4.0% and had a significant clearance of [18F]haloperidol from brain and a higher concentration of [18F]haloperidol in plasma. After withdrawal from medication, [18F]haloperidol clearance from brain became slower than while on medication. These results are discussed in terms of the pharmacokinetics of haloperidol in the human brain and its binding to dopamine D2 receptors and to sigma receptors.     

Antagonizing effect of lithium on the development of dopamine supersensitivity in the tuberoinfundibular system

We investigated wether receptor supersensitivity occurs in the tuberoinfundibular dopaminergic system, as reported in the nigrostriatal and mesolimbic areas. Animals received either haloperidol or saline for 2 weeks. Five days after the last injection of haloperidol, animals pretreated with haloperidol showed a significantly longer lasting inhibition of prolactin (PRL) secretion by apomorphine, compared with the controls. This dopamine receptor supersensitivity was also observed on the 12th, but not the 33rd day after the cessation of haloperidol administration.The effect of lithium on this dopamine supersensitivity in PRL release was investigated. All rat were treated with haloperidol and fed either a diet containing lithium carbonate or a diet without lithium for 2 weeks. Lithium administration with haloperidol resulted in the inhibition of PRL-lowering action of apomorphine at 5 days of withdrawal from haloperidol, indicating that the supersensitivity of dopamine receptors on pituitary lactotrophs were decreased by lithium. This action of lithium may be related to the prophylactic effect of the drug on the manic-depressive disease.     

Withdrawal-associated changes in peripheral nitrogen oxides and striatal cyclic GMP after chronic haloperidol treatment

The irreversible nature of haloperidol-induced tardive dyskinesia suggests a neurotoxic etiology, although the causes are unknown. Since nitric oxide demonstrates neurotoxic as well as neuroprotectant properties, and antipsychotics can inhibit nitric oxide (NO) synthase in vitro, this study investigates the NO-cGMP pathway as a pre-determining factor in chronic haloperidol-associated dyskinesia in rats. Sprague-Dawley rats were administered either water, oral haloperidol (0.25 mg/kg per day po), the guanylyl cyclase-nNOS inhibitor, methylene blue (MB; 5 mg/kg per day ip) or haloperidol plus MB for 3 weeks. In a second protocol, rats received water or haloperidol orally for 17 weeks, followed by 3 weeks withdrawal. Either saline (ip) or MB (ip) was administered for 3 weeks prior to haloperidol withdrawal. Vacous chewing movements (VCMs) were continuously monitored, followed by the determination of serum nitrogen oxides (NO(x)) and striatal cGMP at week 20. Chronic haloperidol engendered significant VCMs, with acute withdrawal resulting in significantly reduced plasma NO(x) and striatal cGMP. Furthermore, NO(x) and cGMP suppression was amplified by pre-withdrawal MB administration. Sub-acute haloperidol similarly induced incremental VCMs, but without effect on NO(x) or cGMP. However, haloperidol plus MB also induced significantly greater VCMs with decreased cGMP compared to haloperidol alone. Thus, NO(x)-cGMP inhibition persists pronounced after long-term haloperidol treatment and withdrawal. MB potentiation of these effects suggests that haloperidol inhibits a NO-dependent neuro-protective response to oxidative stress in the striatum that may pre-determine TD development.     

Haloperidol decanoate. Results of an open-ended multicentric study in chronic psychotic states

An open multicentric study of 196 in-patients was carried out in 9 centres. After an initial stabilization (min. 15 days) with oral haloperidol, patients received haloperidol decanoate IM for at least 24 weeks (or a minimum of 9 injections). Results: - esterification of haloperidol increased the duration of its efficacy (interval between 2 injections: average 4 weeks) without interfering with its therapeutic activity (global appreciation scale, BPRS at each injection and at the end of the treatment); - equivalent quantities of haloperidol injected at a time were 15 to 20 times those administered daily during the initial stabilisation period; - side-effects were not different with haloperidol decanoate as compared to those of the previous period (haloperidol).     

Subchronic buspirone,mesulergine, and ICS 205-930 lack effects on D1 and D2 dopamine binding in the rat striatum during chronic haloperidol treatment

Summary We administered the serotonergic agents buspirone, mesulergine and ICS 205-930 during the last two weeks of a 4-week oral haloperidol chronic treatment regimen and determined dopamine receptor binding and apomorphine-induced stereotypic activity after a drug washout period. D1 receptor binding was not affected by any treatment. Chronic haloperidol treatment produced a significant increase in the density of D2 receptors for all groups, including the groups that were administered combination treatment of haloperidol and serotonergic compounds. Apomorphine-induced stereotypie activity measured 4 days after the last haloperidol treatment was elevated to the same extent for all haloperidol treated groups. Contrary to a previous report, subchronic treatment with buspirone did not significantly reverse neuroleptic-induced D2 receptor up-regulation.     

Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la Tourette's syndrome

The results of this controlled study of the treatment of 57 patients with Gilles de la Tourette's syndrome suggested that both haloperidol and pimozide were more effective than placebo, but that haloperidol was slightly more effective than pimozide. Adverse effects occurred more frequently with haloperidol vs placebo than with pimozide vs placebo, but the frequency was not significantly different for haloperidol compared with pimozide. Clinically significant cardiac effects did not occur at a maximum dosage of 0.3 mg/kg or 20 mg/d for pimozide and 10 mg/d for haloperidol. However, the QTc interval was prolonged during pimozide treatment compared with that during haloperidol treatment, although the values for both medications were not in an abnormal range.     

Haloperidol. Plasma levels and prolactin response as predictors of clinical improvement in schizophrenia: chemical v radioreceptor plasma level assays

The relationship between clinical response of schizophrenic patients to haloperidol and (1) blood levels of the medication, determined by both gas-liquid chromatography (GLC) and radioreceptor (RR) assays, or (2) prolactin response to the medication, was examined in an inpatient study using several fixed doses of haloperidol. Regression analysis disclosed a substantial curvilinear relationship between steady-state GLC-determined plasma haloperidol levels and decrease in Brief Psychiatric Rating Scale (BPRS) Psychosis factor scores; however, no substantial relationship was found between clinical response and RR plasma haloperidol levels or serum prolactin response to haloperidol. Our results suggest that steady-state plasma levels of haloperidol determined by the GLC chemical assay are a better predictor of decreases in BPRS Psychosis factor scores than RR assayed plasma haloperidol levels or prolactin response to haloperidol.     

Reduced haloperidol in the post-mortem brains of haloperidol-treated patients

We measured the concentrations of haloperidol and its reduced alcohol metabolite in human post-mortem tissues with high-performance/liquid chromatography using electrochemical detection. Both haloperidol and reduced haloperidol were detected and quantified in the occipital cortex of nine schizophrenic patients with a history of haloperidol treatment, but not in six samples from nontreated subjects. Reduced haloperidol concentrations were below the detection limit of the assay in several tissues of rats and mice even after 10 days of haloperidol treatment. The results suggest that reduced haloperidol is present in the brains of haloperidol-treated patients at slightly higher concentrations than haloperidol itself. Further studies are warranted to establish the possible biological importance of this haloperidol metabolite.     

Doubleblind evaluation of the antimanic properties of carbamazepine as a comedication to haloperidol

1. Today carbamazepine is the most important alternative to neuroleptic drugs for the treatment of manic psychoses. Often carbamazepine is administered as a comedication to a neuroleptic. 2. A doubleblind study with 20 patients suffering from manic or schizomanic psychoses was performed to determine whether carbamazepine and haloperidol in comedication are more effective than haloperidol alone. 3. Under the tested conditions (24 mg haloperidol p.d.) only the smaller amount of additional medication with levomepromazine in the experimental group gave evidence for the antimanic effect of carbamazepine in combination with haloperidol. 4. Especially the patients with pure manic psychoses seem to benefit from carbamazepine as an adjunct to haloperidol.     

Intramuscular olanzapine and intramuscular haloperidol in acute schizophrenia: antipsychotic efficacy and extrapyramidal safety during the first 24 hours of treatment.

OBJECTIVE: To determine the antipsychotic efficacy and extrapyramidal safety of intramuscular (i.m.) olanzapine and i.m. haloperidol during the first 24 hours of treatment of acute schizophrenia. METHOD: Patients (n = 311) with acute schizophrenia were randomly allocated (2:2:1) to receive i.m. olanzapine (10.0 mg, n = 131), i.m. haloperidol (7.5 mg, n = 126), or i.m. placebo (n = 54). RESULTS: After the first injection, i.m. olanzapine was comparable to i.m. haloperidol and superior to i.m. placebo for reducing mean change scores from baseline on the Brief Psychiatric Rating Scale (BRPS) Positive at 2 hours (-2.9 olanzapine, -2.7 haloperidol, and -1.5 placebo) and 24 hours (-2.8 olanzapine, -3.2 haloperidol, and -1.3 placebo); the BPRS Total at 2 hours (-14.2 olanzapine,-13.1 haloperidol, and -7.1 placebo) and 24 hours (-12.8 olanzapine, -12.9 haloperidol, and -6.2 placebo); and the Clinical Global Impressions (CGI) scale at 24 hours (-0.5 olanzapine, -0.5 haloperidol, and -0.1 placebo). Patients treated with i.m. olanzapine had significantly fewer incidences of treatment-emergent parkinsonism (4.3% olanzapine vs 13.3% haloperidol, P = 0.036), but not akathisia (1.1% olanzapine vs 6.5% haloperidol, P = 0.065), than did patients treated with i.m. haloperidol; they also required significantly less anticholinergic treatment (4.6% olanzapine vs 20.6% haloperidol, P < 0.001). Mean extrapyramidal symptoms (EPS) safety scores improved significantly from baseline during i.m. olanzapine treatment, compared with a general worsening during i.m. haloperidol treatment (Simpson-Angus Scale total score mean change: -0.61 olanzapine vs 0.70 haloperidol; P < 0.001; Barnes Akathisia Scale global score mean change: -0.27 olanzapine vs 0.01 haloperidol; P < 0.05). CONCLUSION: I.m. olanzapine was comparable to i.m. haloperidol for reducing the symptoms of acute schizophrenia during the first 24 hours of treatment, the efficacy of both being evident within 2 hours after the first injection. In general, more EPS were observed during treatment with i.m. haloperidol than with i.m. olanzapine.     

Serum haloperidol levels of schizophrenics receiving treatment for tuberculosis

Serum haloperidol levels were studied in schizophrenic patients with and without antituberculosis therapy, and the effect of these agents on serum haloperidol level was evaluated. Rifampicin caused significant suppression of serum haloperidol levels in all cases studied (n = 7). The serum haloperidol clearance rate was accelerated in patients taking rifampicin, with a shortened half-life (4.9 h) compared with the control group (9.4 h). Among 18 schizophrenic patients receiving isoniazid, three showed significantly elevated serum haloperidol levels. It is possible that isoniazid can elevate haloperidol levels in some patients depending upon some unknown factors. The elevation of serum haloperidol level was though to be due to prolonged clearance of haloperidol secondary to isoniazid interaction with hepatic enzymes involved in drug metabolism. These observations suggest that haloperidol doses in schizophrenic patients receiving rifampicin or isoniazid must be carefully monitored.     

Drug holidays and serum haloperidol levels in schizophrenic patients

Chronic hospitalized schizophrenic patients receiving haloperidol were placed on drug holidays for 2 days. Serum haloperidol levels in these patients decreased to about 60% of the levels seen just prior to the usual morning dosing during the drug holiday. Control subjects not given a drug holiday showed stable day-to-day serum haloperidol levels. The small drop in serum haloperidol blood levels may relate to the lack of relapse observed in such patients.     

Decreased extrapyramidal symptoms with intravenous haloperidol

In a preliminary, prospective study, the intensity of extrapyramidal symptoms was rated in four patients receiving intravenous haloperidol and six patients receiving oral haloperidol. The raters were blind to the route of administration. In this pilot study, the first systematic evaluation of intravenous haloperidol and extrapyramidal symptoms, the patients receiving intravenous haloperidol experienced significantly (p less than .01) less intense extrapyramidal symptoms than did the patients receiving oral haloperidol. The literature on intravenous haloperidol is briefly reviewed, and possible explanations of the lower intensity of extrapyramidal symptoms with intravenous haloperidol in the patients studied are discussed.     

D2-dopamine-receptor occupancy during treatment with haloperidol decanoate

We investigated in an open, explanatory study a total of 24 patients meeting DSM-III-R criteria for schizophrenia. Eighteen patients were treated for at least 4 weeks with a fixed dose of orally administered haloperidol for at least 4 weeks (mean daily dosage ranging from 0.07 to 0.35 mg/kg b.w.), and 6 patients received haloperidol decanoate with a fixed dose for at least 4 months (dosage range 50–150 mg/4 weeks; calculated mean daily dosage ranging from 0.02 to 0.09 mg/kg b.w.). One week after injection of haloperidol decanoate, the single photon emission computed tomography examination was performed. Our data suggest that D₂-dopamine-receptor occupancy of 50 mg/4 weeks haloperidol decanoate 1 week after injection corresponds to an oral dose of 4.5 mg/day haloperidol.     

Positron emission tomography of radioligand binding in porcine striatum in vivo: haloperidol inhibition linked to endogenous ligand release

The ligands N-methylspiperone and haloperidol both bind to D(2)-like dopamine receptors. The competitive nature of the binding over a wide range of haloperidol concentrations and the effect on dopamine release have never been tested in vivo. We determined the competitive interaction between 3-N-[(11)C]methylspiperone ([(11)C]NMSP) and haloperidol binding to striatal dopamine D(2)-like receptors with positron emission tomography (PET) of pig brain. [(11)C]NMSP tomography was performed with haloperidol at five different plasma concentrations maintained constant by programmed infusion. Kinetic parameters of ligand competition for binding in the striatum were determined by deconvolving time-activity curves of the striatum and cerebellum from metabolite-corrected arterial plasma [(11)C]NMSP and haloperidol concentrations. Two types of [(11)C]NMSP-binding sites were evident in the striatum, both saturable by haloperidol administration. The preponderant or primary sites bound [(11)C]NMSP irreversibly, as dopamine D2-like receptors, while the secondary sites bound [(11)C]NMSP reversibly, as do serotonin S2 receptors. Woolf-Hanes plots revealed the predicted approximately linear relationships between the binding indices and the haloperidol plasma concentration. For the irreversible binding sites, this relationship indicated a 50% inhibitory concentration of haloperidol of 2 nM in plasma and a maximum binding capacity of 64 pmol cm(-3) in striatum. For the reversible binding sites, the relationship indicated a 50% inhibitory plasma concentration of haloperidol of 1 nM and a maximum binding capacity of 4.5 pmol cm(-3). Second-order polynomial Eadie-Hofstee-Scatchard plots were consistent with increased competition from an endogenous ligand of the irreversibly binding sites only with increasing doses of haloperidol. At the highest haloperidol dose, this hypothetical endogenous ligand had risen 6-7-fold. We contend that this reveals the release of dopamine by high concentrations of haloperidol.