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PubMed1975

Comparative studies on the effect of lithium and haloperidol on learning and memory.

A comparative study of the effect of lithium and haloperidol on the processes of learning and memory is carried out in experiments for training albino rats in a maze. Haloperidol introduced intraperitoneally 1 h before learning in a dose of 0.2 mg/kg deteriorates the learning and long-term memory, while a dose of 2 mg/kg makes these processes impossible. Introduced immediately after learning, haloperidol shows a tendency towards deterioration in the phase of memory consolidation. When administered 1 h before the long-term memory test, haloperidol inhibits reproduction. Lithium chloride administered in a single dose of 200 or 300 mg/kg before and after learning, has no pronounced effect. A tendency towards impairment of learning and memory is manifested only upon administration of doses of 200 mg/kg for 8 days in succession. The differences in the effects of lithium and haloperidol on learning and memory do not support the assumption that their similar effect on the cAMP system (inhibition of the adenylate cyclase in the brain) is essential for the mechanism of their effect on the central nervous system.

Animals↗

PubMed1975

Behavioral supersensitivity to apomorphine and amphetamine after chronic high dose haloperidol treatment.

Rats administered chronic haloperidol (5 mg/cc) for 2 months exhibited stereotyped gnawing during chronic haloperidol treatment, and after withdrawal from haloperidol, showed significantly greater stereotyped behavior induced by apomorphine or L-amphetamine compared to saline controls. Chronic administration of benztropine mesylate concomitantly with haloperidol reduced the effects of chronic haloperidol on drug induced stereotyped behavior during the withdrawal period.

Amphetamine↗

PubMed1992

Behavioral disinhibition and depression in amphetaminized rats: a comparison of risperidone, ocaperidone and haloperidol.

The mixed serotonin-2/dopamine-D2 antagonists risperidone and ocaperidone were compared with the specific D2 antagonist haloperidol for their ability to antagonize amphetamine (10 mg/kg, s.c.)-induced stereotypy in rats. Four successive stages of amphetamine antagonism were differentiated: 1) disinhibition: reversal of stationary stereotypy into the hyperactivity normally observed with lower doses of amphetamine; 2) inhibition: the first significant reduction of activity; 3) normalization: reduction of activity to the level of nonamphetaminized rats; and 4) suppression: reduction of activity to 50% of the level of nonamphetaminized rats. Ocaperidone and risperidone were equipotent with haloperidol for disinhibition (0.0062-0.011 mg/kg). However, the disinhibition was maintained over a wider dose range with risperidone (factor 84) than with haloperidol (9.0) and ocaperidone (4.1) and was also more pronounced in magnitude with risperidone. Ocaperidone was equipotent with haloperidol for inhibition (0.013-0.025 mg/kg) and normalization (0.074-0.080 mg/kg) but 4.4 times less potent for suppression of activity (0.71 vs. 0.16 mg/kg). Risperidone became progressively less potent than haloperidol: 4.4 times for inhibition, 9.6 times for normalization and 22 times for suppression of activity. The present data are consistent with the hypothesis that serotonin-2 antagonism compensates for the functional consequences of D2 receptor blockade. The implications for the clinical application of the compounds are discussed.

Amphetamine↗

PubMed1992

Haloperidol in schizophrenic children: early findings from a study in progress.

This report presents preliminary findings in an ongoing double-blind, placebo-controlled study of the safety and efficacy of haloperidol in hospitalized schizophrenic children. The subjects are diagnosed schizophrenic by DSM-III-R criteria and admitted to the Bellevue Hospital Children's Inpatient Psychiatric Unit. The study is 10 weeks in duration and employs a crossover design. After a 2-week placebo baseline period, the subjects enter double-blind treatment for 8 weeks, by random assignment receiving either haloperidol for 4 weeks followed by placebo for 4 weeks, or alternatively, placebo for 4 weeks followed by haloperidol for 4 weeks. Dosage, regulated individually, ranges from 0.5 to 10.0 mg/day. To date, of an anticipated 20 subjects, 12 have completed the study. These children, 9 boys and 3 girls, were ages 5.5 to 11.75 years upon study entry. Haloperidol was superior to placebo for reduction of target symptoms with optimal haloperidol dose of 0.5 to 3.5 mg/day (0.02-0.12 mg/kg/day).

Child↗

PubMed2004

Potentiation of haloperidol neurotoxicity in acute hyperthyroidism: report of a case.

Haloperidol has been used extensively for the treatment of many psychiatric illnesses as well as for control of agitated patients. Side effects including anticholinergic, extrapyramidal, sedative side effects as well as neuroleptic malignant syndrome are not unusual. Many factors may contribute to these complications including withdrawal or toxicity, concomitant use of other medications or the underlying illness itself. We report a case without previous history of thyroid disorder sufferring acute manic episode. Haloperidol was prescribed to control psychotic symptoms. Symptoms and signs of extrapyramidal syndrome, catatonia and hyperthyroidism ensued. Prescription of anti-thyroid agents and discontinuation of haloperidol were essential in the successful treatment of this patient. It is hypothesized that underlying hyperthyroidism might have precipitated haloperidol neurotoxicity. Haloperidol might play a role in the exacerbation of hyperthyroidism.

Adult↗

PubMed1992

Further studies on the modulation of regional brain neurotensin concentrations by antipsychotic drugs: focus on haloperidol and BMY 14802.

Acute and chronic treatment with the antipsychotic drug haloperidol or the potential antipsychotic BMY 14802 produce increases in regional neurotensin concentrations which are similar with respect to regional specificity (nucleus accumbens and caudate), time course, magnitude of increase and precedence by an increase in proneurotensin mRNA. The present study characterizes further the effects of haloperidol and BMY 14802 on regional brain neurotensin concentrations and compares certain of their effects to those of sulpiride. Neurotensin concentrations in discrete brain regions of adult, male, Sprague-Dawley rats were determined by radioimmunoassay. Both acute and chronic treatment with BMY 14802 produced significant decreases in the concentration of neurotensin in the frontal cortex. When administered concomitantly, low doses of haloperidol and BMY 14802 produced additive increases in neurotensin content in the nucleus accumbens and caudate. Increases in neurotensin content resulting from concomitant treatment, or with doses which produce maximal effects individually, were not greater than those produced by either drug alone. Concomitant administration of SCH 23390 and sulpiride attenuated the neurotensin increases observed after treatment with sulpiride. Increases in neurotensin concentrations produced by haloperidol and BMY 14802 were not antagonized by SCH 23390. These findings support the hypothesis that haloperidol and BMY 14802 modulate regional neurotensin concentrations through a common or similar mechanism which is distinct from that of sulpiride.

Animals↗

PubMed1992

Haloperidol metabolism in psychiatric patients: importance of glucuronidation and carbonyl reduction.

In 39 patients who received haloperidol regularly we measured plasma concentrations of haloperidol glucuronide (HAL-GL), reduced haloperidol glucuronide (RHAL-GL), haloperidol (HAL), reduced haloperidol (RHAL), and HAL reductase activity in red blood cells. Plasma HAL-GL concentrations were significantly higher than HAL, RHAL, or RHAL-GL concentrations. Concentration ratios of total glucuronide to nonglucuronide and RHAL/HAL ratios were calculated as indices of glucuronidation and reduction capacity in each patient. The plasma glucuronidation ratios showed a significant negative correlation (r = -0.63, p less than 0.001) with the dose, while the reduction ratios showed a positive correlation (r = 0.75, p less than 0.001). No correlations were found between the HAL reductase activity in red blood cells and either the dose or RHAL/HAL. Based on these findings we suggest that glucuronidation of HAL is the major metabolic pathway of HAL in humans and its activity is important in determining steady-state plasma HAL concentrations. Glucuronidation may also be a major contributing factor in the interindividual variability of HAL metabolism.

Adolescent↗

PubMed2005

Effects of tryptophan and valine administration on behavioral pharmacology of haloperidol.

Development of antipsychotics with slight/no extra-pyramidal symptoms (EPS) and/or other side effects is one of the exploring fields of drug research. Haloperidol is a high potency typical neuroleptic used in the treatment of schizophrenia but produces muscles related side effects commonly known as EPS. These effects are not produced following the administration of atypical neuroleptics such as clozapine. A severe side effect of clozapine treatment is however, agranulocytosis. This involves investigation on the mechanism by which a typical neuroleptic acting via serotonergic mechanism tends to produce less or no EPS. The present study was, therefore, designed to determine the effect of serotonin precursor tryptophan and a large neutral amino acid other than tryptophan (valine) on the modulation of haloperidol induced catalepsy and akinesia. Cataleptic effects of the drug and activity reducing effects were monitored on inclined surface and in an activity box or open field respectively. The results are discussed in the context of a role of tryptophan and valine induced changes of brain serotonin in modifying the extrapyramidal and monoaminergic effects of the typical neuroleptic haloperidol. In the present study administration of TRP and valine decreased activity in rats, haloperidol-induced catalepsy' was not modulated by prior administration of tryptophan or valine. Brain serotonin levels were elevated by haloperidol treatment and correlated very well with the behavioral response. These findings suggest a possible serotonergic involvement in neuroleptic induced tardive dyskinesia and an amelioration of the disorder through TRP supplementation.

Animals↗

PubMed1991

Duration of neuroleptic treatment and relapse rate: a 5-year follow-up study with haloperidol decanoate.

The role of neuroleptic drugs in controlling acute psychotic symptoms and reducing relapse is well established. It is the clinical management of chronically disabled patients that has major implications for health care planning. Drug discontinuation studies have indicated that patients with chronic schizophrenia should receive maintenance drug therapy for some years. This was a 5-year follow-up study to assess the long-term effects of depot haloperidol decanoate vs. other neuroleptics in 62 psychotic patients treated in the community. The study indicates that there were more relapses and hospitalization for patients maintained on other neuroleptics than for patients maintained on haloperidol decanoate. The study indicates that haloperidol decanoate even in low dosage is effective maintenance therapy is preventing relapse. Indeed, some of the good responders to haloperidol therapy may have benefitted from lowering the dosage of the drug. It is our experience that haloperidol decanoate is of good value in the management of psychotic illnesses that require long-term treatment. A more controlled longer-term study is needed to confirm our results.

Antipsychotic Agents↗

PubMed1991

Minimal effective dose and relapse--double-blind trial: haloperidol decanoate vs. placebo.

Fifty-six chronic schizophrenic patients were randomized into haloperidol decanoate (HD) or placebo groups for 48 weeks of double-blind treatment. The double-blind trial was preceded by a 15-week single-blind run-in period, during which all patients were treated with 60 mg of HD (approximately corresponding to 3.6 mg orally/day) every fourth week (except for the second injection, which was given after 3 weeks). Eight relapses occurred during the run-in period, and seven other patients refused further participation. The remaining 41 patients were then treated double blind, either with HD, 60 mg/4 weeks (18 patients), or with placebo (23 patients). Two patients (11%) in the HD group and 16 (69%) in the placebo group relapsed during the 48-week double-blind period. The plasma concentrations of haloperidol were measured every fourth week in both groups. Steady state was reached after 11 weeks. The mean steady-state level was 6.3 nmol/L. In the placebo group, a 50% decrease in the mean haloperidol plasma concentration was seen 8 weeks after withdrawal of haloperidol. The haloperidol plasma concentration was a predictor of relapse. There was no statistical difference between the treatment groups regarding extrapyramidal symptoms. More biperiden, however, was used in the HD group, while the placebo patients took more sedatives. The results of this study show that the relatively low and fixed dose of 60 mg of HD every fourth week was superior to placebo in preventing relapse in schizophrenia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

Haloperidol on rat phrenic hemidiaphragm.

The butyrophenone neuroleptic haloperidol (10.65-85.2 microM) blocked the indirectly elicited twitch response of rat phrenic nerve diaphragm preparation. The depression was poorly reversible and was not mediated through dopamine receptors since neither dopamine nor apomorphine could alter the haloperidol blockade. Experiments on the isolated phrenic nerve indicated that the excitability of the nerve was blocked by haloperidol (42.6 microM) and that this blocking effect was minimized in presence of a high concentration of Ca2+ (5 mM) in the bathing fluid. Haloperidol (10.65-85.2 microM) also concentration-dependently inhibited acetylcholine (2.7 microM) contracture, without affecting the potassium chloride (0.5 M) and caffeine (15 mM) contracture. We conclude that haloperidol acts as a local anaesthetic on the motor nerve, probably by affecting calcium channels.

Acetylcholine↗

PubMed1990

Effects of long-term haloperidol treatment on the responsiveness of accumbens neurons to cholecystokinin and dopamine: electrophysiological and radioligand binding studies in the rat.

Cholecystokinin (CCK) and dopamine (DA) coexist in a subpopulation of neurons of the ventral tegmental area projecting to the nucleus accumbens. The present experiments were undertaken to determine the effect of acute and long-term administration of haloperidol on the responsiveness of accumbens neurons to microiontophoretic applications of the sulfated cholecystokinin octapeptide (CCK-8S), kainate (KA), and DA and on the density of CCK, D1, and D2 receptors determined by radioautography. Acute administration of haloperidol (1 mg/kg, i.v.) did not modify the neuronal responsiveness to DA and KA but increased that to CCK-8S. Long-term treatment with haloperidol decanoate (4 mg/kg/week, i.m., for 3-5 weeks) induced a marked increase in the responsiveness to CCK-8S, without noticeable change of that to DA and KA. After a 5 week treatment, significant increases in the amounts of CCK and D2 binding were found in the nucleus accumbens, whereas D1 binding parameters remained unchanged. Since long-term haloperidol treatment results in a depolarization inactivation of A10 dopaminergic neurons, these results suggest that, despite the reduced firing activity of mesolimbic dopaminergic neurons induced by the long-term haloperidol treatment, dopamine is still released in an amount sufficient to maintain a normal neuronal responsiveness of postsynaptic accumbens neurons to DA, whereas the release of CCK is possibly decreased to a greater extent, resulting in an enhanced responsiveness of the neurons to this peptide.

Animals↗

PubMed1990

Effects of long-term administration of haloperidol on electrophysiologic properties of rat mesencephalic neurons.

Haloperidol (1.5-1.7 mg/kg/day) was administered to rats via their drinking water for periods of either 4 weeks or 13 to 14 months, after which the animals were withdrawn from the neuroleptic for 1 or 2 weeks, respectively. Rats given haloperidol for 13 to 14 months exhibited significantly more perioral dyskinesias than controls. Single-unit extracellular recordings were obtained from the substantia nigra and ventral tegmental area in subjects under urethane anesthesia. After 1 month and after 1 year of treatment, a significant decrease in the mean firing rate of substantia nigra pars reticulata neurons was found. Subtle changes in the response of pars reticulata neurons to striatal stimulation were seen after extended haloperidol intake. No consistent effects of haloperidol administration for 4 weeks or 13 to 14 months were found for either the number of spontaneously active dopamine neurons or their firing rates. Histopathologic assessment of tissue from dorsomedial, dorsolateral and ventrolateral sectors of the striatum revealed no significant effect of long-term haloperidol treatment on neuronal cell counts. The results are discussed with reference to neuroleptic-induced tardive dyskinesias.

Animals↗

PubMed1979

Analgesia and haloperidol: a hypothesis.

We have previously reported 10 patient histories involving various intractable pain syndromes where the administration of Haloperidol either eliminated the need for narcotic analgesics or resulted in a significant reduction in narcotic dosage. We are presently undertaking a controlled double-blind evaluation of Haloperidol as an adjunctive treatment for intractable cancer pain. Based upon the reported clinical observations, these findings are discussed from the following aspects: 1. The isomeric similarity of Haloperidol to Meperidine. 2. Dose response between Haloperidol and analgesic effect. 3. The clinical literature regarding the use of Haloperidol for the effective withdrawal or maintenance of narcotic addicts. 4. The analgesic property as it relates to the opiate receptor.

Analgesics↗

PubMed1990

Kinetics and clinical evaluation of haloperidol decanoate loading dose regimen.

We have evaluated the efficacy and safety of different dosing regimens of haloperidol decanoate (HLD). Eighteen patients were evaluated as part of our ongoing Therapeutic Drug Monitoring Program. Diagnoses were chronic schizophrenia (n = 12), bipolar with psychosis (n = 3), and others (n = 3). Patients were assessed prior to each HLD dose using the Clinical Global Impressions (CGI) rating scale. The total monthly HLD dose for our population was calculated based on a target conversion ratio of 20 times the previously administered oral haloperidol dose given in divided doses of 100 mg to 150 mg every 3 to 7 days until the full amount was administered. This HLD dosing pattern was repeated during the second month, but at a lower dose to compensate for drug accumulation. Despite this loading dose paradigm, significantly greater haloperidol plasma concentrations were present during oral haloperidol than during the first month of HLD therapy. This regimen achieves therapeutically equivalent plasma concentrations (Cps) more rapidly following conversion from oral haloperidol than standard dosing procedures. A series of cases and pharmacokinetic simulations are used to illustrate the therapeutic relationship of dosing to plasma concentrations.

Adult↗

PubMed1990

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

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

Adult↗

PubMed1989

[Huntington disease: tetrabenazine compared to haloperidol in the reduction of involuntary movements].

Dopaminergic oversupply relative to intrinsic striatal cell loss is thought to underlie the involuntary movements of Huntington's disease (HD). Tetrabenazine (TBZ) and haloperidol, two antidopaminergic compounds differing in their mechanism of action on the nigrostriatal pathway were compared in 11 HD patients in their ability to decrease the choreatic movements in a single-blind cross-over study. Though improvement in chorea scores over baseline values was greater under TBZ (46.3 +/- 23.4) than haloperidol (28.6 +/- 47.7), the difference did not reach statistical significance (Student t tests). All 11 patients improved to some extent during the TBZ phase, and in 6 it was greater than while under haloperidol. However, haloperidol reduction in the chorea scores was significantly greater in 3 patients, while there was no difference in 2 other cases. Severe depression occurred in 3 patients under TBZ, in one leading to attempting suicide, while tardive dyskinesia complicated haloperidol therapy in 3 patients. The later drug could be an alternative therapy for those patients in whom TBZ provides unsatisfactory control of the choreatic movements, but it might be the drug of choice in cases with associated depressive illness or organic psychosis.

Adult↗

PubMed1989

Mechanism of haloperidol-induced miosis.

Haloperidol administration (iv) has been shown to produce miosis in dogs. In the present study on rabbits, haloperidol administration (iv) produced dose-related miosis but when administered intracerebroventricularly, it failed to produce any change in pupillary size. Higher degree of miosis was observed when haloperidol was administered directly into the anterior chamber of eye. Haloperidol pretreatment failed to significantly modify the mydriasis produced by phenylephrine or atropine. These observations suggest that the miosis produced by haloperidol is a peripheral effect, and also that the miosis is not mediated through the blockade of alpha adrenoceptors of radial muscles or stimulation of cholinoceptors of circular muscles of iris.

Animals↗