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PubMed2005

Olanzapine versus haloperidol in the treatment of agitation in elderly patients with dementia: results of a randomized controlled double-blind trial.

The goal of this study was to compare the efficacy and safety of olanzapine versus haloperidol in the treatment of agitation and aggression in patients with dementia. The subjects were 58 out-patients with dementia and agitation. After baseline assessments and, if necessary, a period of wash-out of a previous antipsychotic drug, they were randomly assigned to 5 weeks of double-blind treatment with either olanzapine or haloperidol. The first 2 weeks were used for dose titration. Subsequently, the patients received a fixed dose of either olanzapine (average dose 4.71 mg) or haloperidol (average dose 1.75 mg) from day 14 to day 35. Both olanzapine and haloperidol decreased agitation significantly (decrease in Cohen-Mansfield Agitation Inventory scores), but there was no significant difference between the two drugs. The two drugs had comparable effects on all secondary outcome measures. They were well tolerated and had a similar side-effect pattern. Our study could not demonstrate the superiority of olanzapine, compared to haloperidol, for the treatment of agitation in patients with dementia.

Aged↗

PubMed1984

Ocular hypotensive actions of haloperidol, a dopaminergic antagonist.

Haloperidol, a dopaminergic antagonist, was found to be very effective in suppressing the intraocular pressure recovery curve of rabbits infused with 20% saline intravenously. Haloperidol was at least equipotent, if not more potent, in lowering IOP and had much longer duration of action compared with timolol maleate. In the cat model, haloperidol increased aqueous humor (AH) outflow initially, followed by a long-lasting suppression of AH formation. Since haloperidol does not block beta-adrenergic receptors and the ophthalmic dose required to lower IOP is only 6.5% of the antipsychotic dose, haloperidol might be a good drug for glaucoma treatment with the possibility of minimal side effects.

Animals↗

PubMed1980

Haloperidol for acute schizophrenic patients. An evaluation of three oral regimens.

The relative efficacy of three oral regimens of haloperidol was compared in a ten-day, double-blind study of 63 acutely ill schizophrenic patients newly admitted to the hospital. One group of patients received 20 mg of haloperidol on day 1, then increasing increments of 20 mg a day, reaching a maximum dosage of 100 mg daily on day 5. Another group received 10 mg of haloperidol on day 1, then increasing increments of 10 mg daily, reaching 100 mg daily on day 10. A third group of patients received a fixed dosage of 10 mg daily for ten days. Haloperidol was well tolerated by the patients; there were no serious adverse reactions. The data indicated that the regimens had similar therapeutic efficacy, suggesting that acutely ill schizophrenic patients respond to a wide range of doses of haloperidol but that onset of response and efficacy are not increased in most patients by providing a high initial loading dosage. Adequate, safe dosage must be determined in each case.

Acute Disease↗

PubMed1984

Akathisia with haloperidol and thiothixene.

We studied the incidence of akathisia in two populations of newly admitted schizophrenic patients: one group was treated with haloperidol and the other group was treated with thiothixene hydrochloride. Within six hours after taking a 5-mg test dose of haloperidol, 40% of the patients experienced akathisia; during maintenance treatment with 10 mg of haloperidol taken at bedtime, 75% of the patients experienced akathisia by the seventh day. With thiothixene hydrochloride (0.22-mg/kg test dose; 0.44-mg/kg maintenance dose), the respective percentages were 20% and 46%. The akathisia experienced after administration of the test of haloperidol dose was not mild or inconsequential; 28% of the patients experienced moderate, 17% of the patients experienced severe, and 22% of the patients experienced very severe akathisia. Akathisia with haloperidol could not be suppressed completely in half of the patients. Treatment-resistant akathisia was experienced as anxiety and depression. We believe these tallies to be important because akathisia causes much misery and often goes undiagnosed.

Adult↗

PubMed1986

Progress in pharmacotherapy of borderline disorders. A double-blind study of amitriptyline, haloperidol, and placebo.

In symptomatic patients with borderline disorder, we conducted a double-blind, placebo-controlled trial of haloperidol and amitriptyline hydrochloride to test the differential efficacy of medication against the affective and schizotypal symptoms that characterize the disorder. Sixty-one patients, diagnosed by the Diagnostic Interview for Borderline of Gunderson et al, completed randomized trials of haloperidol (n = 21), amitriptyline (n = 20), and placebo (n = 20). Medications were given in dose ranges of 4 to 16 mg for haloperidol (mean, 7.24 mg) and 100 to 175 mg for amitriptyline hydrochloride (mean, 147.62 mg) for five-week periods, with weekly self-rated and observer-rated measures of mood, schizotypal symptoms, and global functioning. Haloperidol was superior to both amitriptyline and placebo on a composite measure of overall symptom severity, with no difference between amitriptyline and placebo. Haloperidol produced significant improvement on a broad spectrum of symptom patterns, including depression, anxiety, hostility, paranoid ideation, and psychoticism. In contrast, amitriptyline was minimally effective, with small gains limited to some areas of depressive content. The magnitude of change tended to be modest and was more apparent in self-rated than observer-rated measures.

Adolescent↗

PubMed2001

Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized and double-blind comparison.

BACKGROUND: Despite the demonstrated efficacy of clozapine in severely refractory schizophrenia, questions remain regarding its efficacy for primary negative symptoms, comparison with a moderate dose of a first-generation antipsychotic, and adverse effects during a longer-term trial. This study examined its efficacy in partially responsive, community-based patients, compared clozapine with moderate-dose haloperidol, and extended treatment to 6 months. METHODS: Randomized, double-blind, 29-week trial comparing clozapine (n = 37) with haloperidol (n = 34). Subjects with schizophrenia who were being treated in community settings at 3 collaborating clinical facilities were enrolled. RESULTS: Subjects treated with haloperidol were significantly more likely to discontinue treatment for lack of efficacy (51%) than were those treated with clozapine (12%). A higher proportion of clozapine-treated subjects met an a priori criterion of improvement (57%) compared with haloperidol-treated subjects (25%). Significantly greater improvement was seen in symptoms of psychosis, hostile-suspiciousness, anxiety-depression, thought disturbance, and total score measured on the Brief Psychiatric Rating Scale. No differences were detected in negative symptoms using the Brief Psychiatric Rating Scale or the Schedule for Assessment of Negative Symptoms. Subjects treated with clozapine experienced more excess salivation, dizziness, and sweating and less dry mouth and decreased appetite than those treated with haloperidol. CONCLUSIONS: Compared with a first-generation antipsychotic given in a moderate dose, clozapine offers substantial clinical benefits to treatment-refractory subjects who can be treated in the community. Advantages are seen in a broad range of symptoms but do not extend to negative symptoms.

Adult↗

PubMed1996

Involvement of adenosine and glutamate receptors in the induction of c-fos in the striatum by haloperidol.

The psychostimulant drugs amphetamine and cocaine induce the expression of immediate early genes, such as c-fos, in the striatum via D1 dopamine receptor activation. This occurs primarily in the striato-nigral neurons. Conversely, neuroleptic drugs, such as haloperidol, which block D2-type dopamine receptors, induce c-fos expression in striatal neurons projecting to the globus pallidus. In order to gain insight into the neurochemical substrates of neuroleptic-induced c-fos expression, we examined the effects of adenosine A2 and N-methyl-D-aspartate (NMDA) receptor antagonists as well as inhibition of nitric oxide synthase, on haloperidol-induced Fos immunoreactivity in the striatum. While blockade of D1 receptors had no effect on haloperidol-induced Fos expression, adenosine A2 receptor antagonists decreased the number of neurons in the striatum expressing haloperidol-induced Fos by half. NMDA receptor antagonists also potently blocked the induction of Fos immunoreactivity by haloperidol, while inhibition of nitric oxide synthase activity had no effect. These results indicate that in the presence of a dopamine D2 antagonist, Fos expression in striato-pallidal neurons is mediated in part through activation of A2 receptors by adenosine, and via NMDA receptor activation by glutamate.

Animals↗

PubMed1996

Activation of corticostriatal pathway leads to similar morphological changes observed following haloperidol treatment.

Treatment with haloperidol, a dopamine receptor D-2 antagonist, for one month resulted in an increase in the mean percentage of asymmetric synapses containing a discontinuous, or perforated, postsynaptic density (PSD) [Meshul et al. (1994) Brain Res., 648:181-195] and a change in the density of striatal glutamate immunoreactivity within those presynaptic terminals [Meshul and Tan (1994) Synapse, 18:205-217]. We speculated that this haloperidol-induced change in glutamate density might be due to an activation of the corticostriatal pathway. To determine if activation of this pathway leads to similar morphological changes previously described following haloperidol treatment, GABA (10(-5) M, 0.5 microliters) was injected into the thalamic motor (VL/VM) nuclei daily for 3 weeks. This treatment resulted in an increase in the mean percentage of striatal asymmetric synapses containing a perforated PSD and an increase in the density of glutamate immunoreactivity within nerve terminals of asymmetric synapses containing a perforated or non-perforated PSD. Subchronic injections of GABA into the thalamic somatosensory nuclei (VPM/VPL) had no effect on the mean percentage of synapses with perforated PSDs but resulted in a small, but significant, increase in density of glutamate immunoreactivity. Using in vivo microdialysis, an acute injection of GABA (10(-5) M, 15 microliters) into VL/VM resulted in a prolonged rise in the extracellular level of striatal glutamate. The increase in asymmetric synapses with perforated PSDs and in glutamate immunoreactivity within nerve terminals of the striatum following either subchronic haloperidol treatment or GABA injections into VL/VM suggest that an increase in glutamate release may be a common factor in these two experiments. It is possible that the extrapyramidal side effects associated with haloperidol treatment may be due, in part, to an increase in release of glutamate within the corticostriatal pathway.

Animals↗

PubMed1996

Striatal c-fos levels do not correlate with haloperidol-induced behavioral supersensitivity.

Striatal c-fos levels and stereotyped behavior have been evaluated in chronically haloperidol-treated rats which received subsequent subacute dopamine (DA) agonist treatment to investigate the possible relationship between striatal c-fos and behavioral supersensitivity. Haloperidol treatment (1 mg/kg/day for 21 days) increased apomorphine-induced stereotypies but did not modify striatal c-fos levels. The subacute administration of the DA D-1 agonist SKF38393 (10 mg/kg/day for 5 days) and the combination of the D-1 agonist with the D-2 agonist quinpirole (1 mg/kg/day for 5 days) attenuated apomorphine-induced stereotypies after haloperidol pretreatment. The administration of quinpirole alone, however, did not modify the response to haloperidol. All DA agonists significantly increased c-fos levels after apomorphine injection. The dissociation between haloperidol-induced behavioral supersensitivity and striatal c-fos levels observed in this study suggests that mechanisms different from striatal c-fos induction might be involved, and that striatal c-fos levels are not a good marker of behavioral supersensitivity expression.

Animals↗

PubMed1998

Effects of risperidone and haloperidol on tachykinin and opioid precursor peptide mRNA levels in the caudate-putamen and nucleus accumbens of the rat.

We investigated whether the two output pathways of the striatum are differently affected by the novel atypical drug risperidone and the conventional typical antipsychotic drug haloperidol. To this end, changes in mRNA levels of preproenkephalin-A, preproenkephalin-B, and preprotachykinin were determined in the rat striatum following chronic drug treatment for 14 days, using quantitative in situ hybridization. Furthermore, we studied the contribution of the dopamine D2 and serotonin 5-HT2A antagonist components of risperidone in establishing its effects on neuropeptide mRNA levels in the striatum. The results showed that both risperidone and haloperidol had major effects on the preproenkephalin-A mRNA and thus on the indirect striatal output route, whereas they had minor effects on preproenkephalin-B and preprotachykinin mRNA, contained by the direct output route. When both drugs were administered in the same dose, preproenkephalin-A mRNA was much more elevated by haloperidol than by risperidone. However, when doses of risperidone and haloperidol were modified to attain comparable dopamine D2 receptor occupancy, the drugs had comparable effects on preproenkephalin-A mRNA levels. It was further found that 5-HT2A/C receptor blockade with ritanserin had only modest effects on preproenkephalin-B and preprotachykinin mRNA levels and did not affect preproenkephalin-A mRNA levels. We conclude that risperidone and haloperidol, administered in the same dose, differently affect the striatal output routes. Furthermore, the results suggest that the effects of risperidone on neuropeptide mRNA levels are fully accounted for by its D2 antagonism and that no indication exists for a role of 5-HT2A receptor blockade in this action.

Animals↗

PubMed1999

Enhancement of N-methyl-D-aspartate (NMDA) immunoreactivity in residual dendritic spines in the caudate-putamen nucleus after chronic haloperidol administration.

Glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype in the caudate-putamen nucleus (CPN) have been implicated in the adverse motor effects produced by chronic administration of the typical antipsychotic drug haloperidol. To determine the functionally relevant sites, we examined the electron microscopic immunocytochemical localization of the R1 receptor subunit (NMDAR1) in the dorsolateral CPN of rats receiving 4 months of biweekly depot intramuscular injections of either haloperidol or vehicle. In all animals, NMDAR1 immunoreactivity was seen mainly in dendritic spines, but was also present in a few somata and dendrites of spiny neurons, axon terminals, and glia. In comparison with controls, the dissector stereological analysis showed a significant reduction in the numerical density of total NMDAR1-labeled and unlabeled dendritic spines in the dorsolateral CPN after haloperidol administration. When labeled spines were identified separately based exclusively on the presence of immunoreactivity within a single plane of section, there was, however, a significant increase in the numerical density of NMDAR1-containing spines in haloperidol vs. control animals. This increase was not seen using a classic dissector, suggesting that the enhancement was mainly attributed to more frequent detection of spines having higher levels of NMDA immunoreactivity. Our results are the first to identify dendritic spines in the dorsolateral CPN as preferential sites for the regulated expression of NMDA receptors following chronic administration of haloperidol.

Animals↗

PubMed1981

Specific antiemetics for specific cancer chemotherapeutic agents: haloperidol versus benzquinamide.

Sixty-four patients receiving cancer chemotherapy known to induce severe emesis entered a randomized double-blind study of the antiemetic efficacy of haloperidol (Haldol) and benzquinamide (Emetecon). Patients preferred haloperidol for control of emesis induced by cis-platinum (78 vs. 22%) or nitrogen mustard (67 vs. 16%). Patients receiving Doxorubicin preferred benzquinamide by a small margin (46 to 38%). Individual patients who experienced no relief with their first antiemetic (13 of 15) usually got some relief with the other after crossover. Haloperidol was more effective than benzquinamide (54 vs. 29%) in patients previously unrelieved by prochlorperazine (Compazine). Complete relief of vomiting was obtained in 14 of 45 patients receiving haloperidol but only five of 41 patients receiving benzquinamide experienced no vomiting, again dependent on the anticancer agent used. Although haloperidol is a more effective antiemetic agent overall, efficacy is related to the anticancer treatment and probably to individual patient characteristics.

Adult↗

PubMed2000

Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration.

The antipsychotics haloperidol and risperidone are widely used in the therapy of schizophrenia. The former drug mainly acts on the dopamine (DA) D(2) receptor whereas risperidone binds to both DA and serotonin (5HT) receptors, particularly in the neurons of striatal and limbic structures. Recent evidence suggests that neurotrophins might also be involved in antipsychotic action in the central nervous system (CNS). We have previously reported that haloperidol and risperidone significantly affect brain nerve growth factor (NGF) level suggesting that these drugs influence the turnover of endogenous growth factors. Brain-derived neurotrophic factor (BDNF) supports survival and differentiation of developing and mature brain DA neurons. We hypothesized that treatments with haloperidol or risperidone will affect synthesis/release of brain BDNF and tested this hypothesis by measuring BDNF and TrkB in rat brain regions after a 29-day-treatment with haloperidol or risperidone added to chow. Drug treatments had no effects on weight of brain regions. Chronic administration of these drugs, however, altered BDNF synthesis or release and expression of TrkB-immunoreactivity within the brain. Both haloperidol and risperidone significantly decreased BDNF concentrations in frontal cortex, occipital cortex and hippocampus and decreased or increased TrkB receptors in selected brain structures. Because BDNF can act on a variety of CNS neurons, it is reasonable to hypothesize that alteration of brain level of this neurotrophin could constitute one of the mechanisms of action of antipsychotic drugs. These observations also support the possibility that neurotrophic factors play a role in altered brain function in schizophrenic disorders.

Animals↗

PubMed2006

Comparative efficacy of risperidone versus haloperidol on behavioural and psychological symptoms of dementia.

BACKGROUND: Behavioural and psychological symptoms of dementia (BPSD) cannot be regarded as a single clinical syndrome, but rather as a heterogeneous group of symptoms, each of which can be considered as possible targets for therapy. OBJECTIVE: To compare the efficacy of risperidone and haloperidol on specific manifestations of BPSD. METHODS: A post-hoc analysis was conducted using data from an 18-week, randomized, double-blind, crossover head-to-head trial of risperidone vs haloperidol in treating 114 nursing-home residents with BPSD. Dependent variables were item scores of the Korean versions of the Behavioural Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD-K) and Cohen-Mansfield Agitation Inventory (CMAI-K). RESULTS: On the BEHAVE-AD-K, risperidone was significantly more effective than haloperidol in treating wandering (p = 0.0496), agitation (p = 0.0091), diurnal rhythm disturbances (p = 0.0137), anxiety regarding upcoming events (p = 0.0002), and other anxieties (p = 0.0088). On the CMAI-K, risperidone was significantly more effective in treating physical sexual advances (p = 0.0202), pacing and aimless wandering (p = 0.0123), intentional falling (p = 0.0398), hoarding things (p = 0.0499), performing repetitious mannerisms (p = 0.0048), repetitive sentence or questions (p = 0.0025), complaining (p = 0.0101), and negativism (p = 0.0027). Haloperidol was not significantly superior to risperidone on any individual item in either scale. CONCLUSIONS: When comparing treatment effects on individual symptoms frequently occurring in patients with dementia, risperidone significantly improved symptoms of agitation, wandering, diurnal rhythm disturbance and anxieties, among other symptoms, compared with haloperidol.

Aged↗

PubMedDate not supplied

Comparative trial of the antiemetic effects of THC and haloperidol.

A prospective, randomized and double-blinded trial of the comparative effects of delta-9-tetrahydrocannabinol (THC) and haloperidol (H) was begun in February 1980. Patients were randomized to initially receive either THC or haloperidol with cross-over to the other agent after two courses. All patients evaluated efficacy and toxicity of each agent and those patients completing the study expressed a preference for either THC or haloperidol. All patients are receiving chemotherapeutic agents known to induce severe vomiting (cis-platinum, nitrogen mustard, or doxorubicin) or have a history or retching with chemotherapy. Fifty-two patients are evaluable as of October, 1980. THC and haloperidol were equally effective in controlling nausea and vomiting as judged by number of vomiting episodes, patient evaluation of efficacy, and patient preference. About 10% of patients had complete control of vomiting and a third had less than five episodes. Patients failing one of the antiemetics had good control with the other about half the time. Toxicities from THC were less well tolerated than those from haloperidol, but most patients had no serious side effects. Nonoverlapping toxicities and efficacy raise the possibility that a combination of the agents might be worthwhile.

Adult↗

PubMed1981

Tissue distribution studies of [18F]haloperidol, [18F]-beta-(4-fluorobenzoyl)propionic acid, and [82Br]bromperidol by external scintigraphy.

Tissue distribution studies of [18F]haloperidol and [82Br]bromperidol, two potent neuroleptic drugs, were performed in rats by serial sacrifice. The usefulness of external scintigraphy in obtaining tissue distribution data in large animals is demonstrated by the tissue distribution of [18F]haloperidol in rhesus monkeys. Both serial sacrifice and external scintigraphic studies demonstrated that uptake of the two drugs after intravenous administration into their target organ, the brain, was very fast and that the ratio of brain to blood levels was high throughout the 2-hr observation. Bromperidol appeared to reach peak brain levels faster than its chloro analog, haloperidol. Both bromperidol and haloperidol concentrated overwhelmingly in the rat lung. Haloperidol also showed a high affinity for the monkey lung. The disposition pattern in rats of [18F]-beta-(4-fluorobenzoyl)propionic acid, an apparent intermediate in butyrophenone metabolism, was entirely different from that of the parent drugs. This metabolite did not concentrate in the rat brain.

Animals↗

PubMed2002

Spatial and temporal profile of haloperidol-induced immediate-early gene expression and phosphoCREB binding in the dorsal and ventral striatum of amphetamine-sensitized rats.

To determine if D(2) dopamine receptor-mediated nuclear signaling is altered during the development of amphetamine sensitization, we examined the expression of immediate-early gene (IEG) products, Fos, Jun, and Fos-related antigen (FRA), in both controls and amphetamine-sensitized rats after a challenge with the D(2) antagonist haloperidol. When chronic saline- or amphetamine (5 mg/kg, i.p. for 14 days)-treated rats were challenged with 2 mg/kg haloperidol at withdrawal day 3 (w3), more 35-kDa FRA was induced in the ventral striatum of the control group than in the amphetamine-treated rats. In contrast, more Jun and 35-kDa FRA were expressed in the ventral striatum of the amphetamine-treated group than in the controls when haloperidol was given at w10. Topographical analyses indicate that the decrease in FRA immunoreactive neuronal density in amphetamine-treated rats at w3 were located in the dorsolateral caudate/putamen and the nucleus accumbens shell and core subregions. Conversely, the increase in Jun-immunoreactive neurons in amphetamine-treated rats at w10 was observed in the dorsolateral caudate/putamen; in the case of the FRAs, the increase was observed in the nucleus accumbens shell. In addition, the time-dependent profile of IEG expression paralleled the activation of an upstream regulator, cAMP-response element binding protein, in the ventral striatum after haloperidol treatment. These neurochemical changes may be associated with behavioral plasticity, since amphetamine-treated rats displayed a lower amount of locomotor activity when exposed to a novel environment at w3, but had recovered at w10. Overall, the current study reveals that there is a distinct temporal and spatial profile of haloperidol-induced IEG expression and/or CREB phosphorylation in amphetamine-treated rats, suggesting that there is a critical transition between the early and late withdrawal periods.

Amphetamine↗

PubMed1991

Effects of CI-943, a potential antipsychotic drug, and haloperidol on regional brain neurotensin concentrations.

Treatment with efficacious antipsychotic drugs such as haloperidol increases the concentrations of neurotensin (NT) in the nucleus accumbens and caudate nucleus of the rat. These increases in NT concentrations may be associated with the therapeutic and/or side effects of these drugs. CI-943, a novel compound without appreciable affinity for dopamine-binding sites, produces behavioral effects in animals, which suggest that it may possess antipsychotic activity. This study evaluated the effects of subchronic treatment (3 weeks) with CI-943 or haloperidol on regional brain NT concentrations in rats. Haloperidol treatment (1 mg/kg) produced significant increases in the concentrations of NT in the nucleus accumbens and caudate nucleus but not in the other brain regions studied. Like haloperidol, CI-943 (40 mg/kg) increased NT concentrations in the nucleus accumbens and caudate but differed in that CI-943 produced significantly greater increases in NT concentration in the caudate than haloperidol and also increased NT content in the substantia nigra/ventral tegmental area and hypothalamus. The regional specificity of the NT alterations produced by chronic treatment with CI-943, a nondopamine receptor ligand, was similar to that previously reported after treatment with multiple doses of methamphetamine.

Animals↗