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PubMed1999

The effects of classic antipsychotic haloperidol plus the extract of ginkgo biloba on superoxide dismutase in patients with chronic refractory schizophrenia.

OBJECTIVES: To explore the association between schizophrenic symptoms and superoxide dismutase (SOD), and to investigate the effect of classic antipsychotic haloperidol plus the extract of Ginkgo biloba (EGb) on SOD. METHODS: In 54 patients with chronic refractory schizophrenia, 27 were treated with haloperidol plus EGb (group 1), and the rest received haloperidol plus placebo (group 2). Superoxide dismutase (SOD) levels of these patients were measured before and after treatment and compared with the levels of 25 healthy volunteers. Therapeutic efficacy was equated with a change in clinical rating scores assessed by standardized measurement tools including the Scale for Assessment of Positive Symptoms (SAPS) and the Scale for Assessment of Negative Symptoms (SANS). RESULTS: Patients in group 1 improved significantly as demonstrated by scores from both SAPS and SANS, while those in group 2 only by scores from SANS. Assessed by SAPS, the response of patients receiving haloperidol plus EGb was more significant than those receiving haloperidol only. SOD levels before treatment in all patients were significantly higher than those in normal controls. After treatment, SOD levels decreased significantly in group 1 but not in group 2. In addition, before treatment, SOD levels in all patients correlated significantly with SAPS score. The levels of SOD measured before treatment were also correlated with the improvement of patients as measured by SAPS and SANS after 12 weeks. CONCLUSIONS: EGb may enhance the efficacy of classic antipsychotic haloperidol on schizophrenia, especially on positive symptoms. It may work through an antioxidant efficacy that is involved in the therapeutic mechanism.

Adult↗

PubMed1992

Effects of age and isolation on the evolution of catalepsy during chronic haloperidol treatment.

Sixteen young (5 months) and 16 old (20-24 months) male Wistar rats, housed together or in individual cages were observed for cataleptic behavior 10, 20 and 30 days after the beginning of chronic haloperidol treatment (1.0 mg/kg, twice daily, for 30 days). Catalepsy was measured by the bar test. Age increased the duration of haloperidol-induced catalepsy of isolated and group-housed rats in the three observation sessions (old-isolated = 7.4 +/- 0.2; old-group housed = 7.5 +/- 0.1; young-isolated = 6.3 +/- 0.2; young-group housed = 6.8 +/- 0.2 In seconds in session 1, for example). Conversely, isolation did not modify the sensitivity to the cataleptic effect of haloperidol. Even more important, no differences in duration of haloperidol-induced catalepsy were observed among the three sessions for each group. The results indicate that under the experimental conditions employed the animals did not develop tolerance nor sensitization to haloperidol-induced catalepsy. In addition, neither age nor isolation modified the absence of effects of repeated haloperidol treatment on the catalepsy behavior of rats.

Aging↗

PubMed1992

[The threshold lowering effects of chronic treatment with haloperidol on beta-carboline derivative-induced tonic convulsion].

To clarify a relationship between dopamine neuron and purine, GABA or benzodiazepine system, we have studied the changes in the threshold of tonic convulsion induced by each antagonist after chronic treatment with haloperidol in mice. Mice were given haloperidol (1 mg/kg, sc) once a day for 19 d and challenged with caffeine (an adenosine receptor antagonist), beta-DMCM (beta-carboline derivative: as a benzodiazepine receptor antagonist), picrotoxin (a Cl- channel blocker) or bicuculline (a GABAa receptor antagonist) 30 min, 24 h and 48 h after the last injection of haloperidol. Only the threshold of beta-DMCM-induced tonic convulsion was lowered and it was reversed 7 d after the last injection. The beta-DMCM-induced convulsions on 2 d withdrawal were reversed by diazepam (2.5 mg/kg, ip; a benzodiazepine receptor agonist), Ro15-1788 (5.0 mg/kg, ip; as like a benzodiazepine receptor partial agonist), muscimol (2.0 mg/kg, ip; a GABAa receptor agonist) or apomorphine (0.25 and 2.0 mg/kg, ip; a dopamine receptor agonist). These results suggest that the lowering effect of chronic haloperidol on seizure threshold may be involved in the development of tolerance to haloperidol. It may implicate in direct interactions between benzodiazepine and dopamine or GABA systems but may not between dopamine and GABA neurons in development of lowering seizure threshold following chronic haloperidol treatment.

Animals↗

PubMed1991

Possible mechanism of haloperidol-induced enhancement of memory retrieval.

The effects of pretest administration of haloperidol on retention of a step-through passive avoidance task was studied with a 3-day training and retention test interval. Haloperidol at doses of 0.3 mg/kg and 0.5 mg/kg i.p. enhanced memory retrieval. This effect of haloperidol is possibly mediated by interaction with alpha 2-adrenergic receptors, that results in increasing the noradrenergic transmission, or it could be due to direct interaction with dopamine receptors. Yohimbine (2.5 mg/kg) also enhanced memory retrieval, as shown by haloperidol. Clonidine (0.05 mg/kg) significantly antagonized the effect of haloperidol on memory retrieval. Scopolamine (0.5 mg/kg) did not have any effect on enhancement of memory produced by haloperidol.

Animals↗

PubMed1991

The effect of benztropine on haloperidol-induced dystonia, clinical efficacy and pharmacokinetics: a prospective, double-blind trial.

Twenty-nine inpatients with major psychotic disorders were treated for 14 days with a clinician-determined dose of haloperidol and with either benztropine or placebo given by double-blind random assignment on days 1 through 7. No differences were noted in haloperidol mean dose, haloperidol blood levels, or BPRS scores during the first seven days between benztropine (N = 14) and placebo (N = 15) groups. Benztropine-treated patients demonstrated increased dry mouth and diminished sweat and a non-significantly lower rate of dystonia compared to placebo (14% vs. 33%). Dystonic patients were significantly younger than nondystonic patients, but did not differ in haloperidol mean dose or plasma concentration. The effect of benztropine on the incidence of dystonia was consistent with other studies, which, when analyzed together, demonstrate the efficacy of anticholinergic prophylaxis. The relatively low incidence of anticholinergic side effects, coupled with the lack of effect on haloperidol blood levels or antipsychotic efficacy, suggest that moderate doses of benztropine in conjunction with haloperidol are a rational approach for the treatment of acute psychosis in young patients.

Adult↗

PubMed1990

Chronic treatment with SCH 23390 and haloperidol: effects on dopaminergic and serotonergic mechanisms in rat brain.

Effects of chronic administration (18 days) with SCH 23390 (0.1 or 0.5 mg/kg/day s.c.) and haloperidol (1 mg/kg/day s.c.) on dopamine and serotonin synthesis and metabolism in discrete dopaminergic and serotonergic nuclei of rat brain were studied. Additionally, the effects of these treatments on dopamine D-1 and D-2 receptor characteristics in rat caudate-putamen were investigated. Chronic administration with both dose regimens of SCH 23390 decreased DA metabolism significantly (basal homovanillic acid concentrations) in nucleus caudatus. In another set of experiments dopamine synthesis (rate of accumulation of 3,4-dihydroxyphenylalanine after 3,4-dihydroxyphenylalanine-decarboxylase inhibition) was reduced significantly only in nucleus accumbens after the higher SCH 23390 dose regimen. In turn, chronic administration with haloperidol decreased basal dopamine metabolism and synthesis in nucleus caudatus and nucleus accumbens. Chronic haloperidol, but not SCH 23390, treatment induced a clear-cut increase in [3H]spiperone binding in caudate-putamen. Interestingly, neither SCH 23390 nor haloperidol treatments affected [3H]SCH 23390 binding in caudate-putamen. SCH 23390 and haloperidol had no significant effects on serotonin synthesis and metabolism in serotonergic and dopaminergic areas. In conclusion, the classical antipsychotic drug, haloperidol, clearly decreases dopamine turnover in nigrostriatal and mesolimbic dopaminergic systems. The D-1 antagonist, SCH 23390, also decreases dopaminergic activity in nigrostriatal and mesolimbic systems although DA synthesis and metabolism are affected to different degrees in nucleus caudatus and nucleus accumbens. Therefore, we suggest that if D-1 antagonists such as SCH 23390 show antipsychotic activity in clinical studies, they may not be free of extrapyramidal side-effects.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1989

Device for monitoring locomotor activity of 120 animals: motility of offspring of dams exposed to haloperidol.

A device using four infra-red light photocells per cage which monitor simultaneously the motility of 120 individual rodents, was developed at our institute. The measuring interval can be chosen freely, the starting time may be set freely and the test may last several weeks. The motility of the offspring (day 35-39) of dams exposed to the neuroleptic haloperidol during lactation was investigated, because of the important stage of the brain development in the neonatal age and of the relatively high concentration of haloperidol in the milk. Mice dams were treated sc. with a single dose (1.5 mg/kg) of haloperidol postnatally on day 3 to 6. Compared to the controls the body weight gain of treated (via milk) pups was reduced (controls = 72%, haloperidol = 30%) and the mortality was higher (controls = 10%, haloperidol = 77%) during the treatment period. The quantitative and qualitative analysis of the locomotor activity from day 35 to day 39 shows a distinct shift in the kind of motility: the locomotor activity of haloperidol offspring is significantly reduced while the number of activity phases is increased. It appears that there is a persistent alteration in the central nervous system that leads to a higher frequency but a lower efficacy of activity.

Animals↗

PubMed1989

Effects of acute and chronic clozapine and haloperidol on in vitro release of acetylcholine and dopamine from striatum and nucleus accumbens.

The purpose of this investigation was to determine if striatal or nucleus accumbens dopamine (DA) release, ACh release or DA receptor function were altered by acute and chronic haloperidol or clozapine treatment in a manner consistent with the reported pharmacological effects of each drug on A9 and A10 DA cell bodies and projection areas, when experiments were performed without a drug-free, or washout, period after drug treatment. The release of neurotransmitters reported here was evaluated using a slice-superfusion assay system. Transmitter release was induced either by an electrical field (for DA and ACh) or by application of either amphetamine or amfonelic acid (DA only). Dopaminergic receptor function was assessed by inhibiting electrically stimulated ACh release with in vitro TL-99 (a dopaminergic agonist) and by reversing that inhibition with in vitro neuroleptics or with ex vivo experimental paradigms (the in vitro analysis of transmitter release subsequent to in vivo drug administration). These data suggest that although there are differences between haloperidol and clozapine, there is no difference between the degree of postsynaptic DA receptor blockade produced that can be attributed to the duration of neuroleptic treatment. Chronic clozapine (20 mg/kg x 21 days) reversed TL-99-induced inhibition of ACh release in the nucleus accumbens only, whereas chronic haloperidol (0.5 mg/kg x 21 days) produced a similar reversal in both brain areas. One possible explanation for the lack of effect of chronic clozapine treatment in the striatum is that carrier-mediated (amphetamine-stimulated) DA release is enhanced in the striatum but not in the nucleus accumbens, suggesting that the potential DA receptor block in the striatum may be compromised by enhanced striatal DA levels. Acute haloperidol (0.5 mg/kg) was found to increase electrically stimulated ACh release in the striatum and DA release in the nucleus accumbens. Tolerance developed in the striatum, but not the nucleus accumbens, with repeated administration. However, acute clozapine had no effect on ACh release in either area, but it was found to enhance DA release in the striatum, an effect to which tolerance developed with chronic administration. Further, comparison of these data with data obtained using haloperidol and clozapine in vitro suggests that it is unlikely that these effects are due to residual drug still present in these tissues at the time of experimentation. These data are discussed with regard to electrophysiological and pharmacological differences observed between clozapine and haloperidol on the activity of A9 and A10 DA cells after chronic neuroleptic treatment.

Acetylcholine↗

PubMed1988

The relationship of haloperidol concentrations to therapeutic response.

Data from pharmacokinetics studies that examined the relationship of haloperidol serum concentrations and therapeutic response in schizophrenic patients were reexamined utilizing the method of logistic regression analysis. A linear rather than a curvilinear relationship was obvious between serum haloperidol concentration and therapeutic response according to both the regression analysis and inspection of the distribution of the data. It was concluded that a serum haloperidol concentration in the range of 9 to 15 ng/ml was associated with a 30% decrease in the total Brief Psychiatric Rating Scale (BPRS) score. Haloperidol concentrations above these appear unlikely in the majority of patients to produce any additional reduction of symptoms. The BPRS psychosis factor finding suggested an analogous finding for serum haloperidol concentrations between 12 and 17 ng/ml. The analyses suggest that the probability of response to haloperidol seems to reach a point of diminishing return at concentrations of approximately 9 to 17 ng/ml. Serum concentrations above this limit do not appear to either decrease or increase the probability of response.

Adolescent↗

PubMed1986

A comparative trial of haloperidol decanoate and fluphenazine decanoate in chronic schizophrenic patients.

A twenty-week double-blind study was conducted to compare the efficacy and side-effect profile of haloperidol decanoate and fluphenazine decanoate, both given four-weekly, in fifty-one chronic schizophrenic patients. The mean dose of fluphenazine decanoate was 84 mg compared to 122 mg for the haloperidol decanoate group--suggesting a potency ratio of 1.0 : 1.4 in this study population. The CPRS sub-scale for schizophrenic symptoms showed a statistically significant improvement (p. less than 0.05) for the haloperidol decanoate group after twenty weeks treatment. A significant difference favouring haloperidol decanoate (p. less than 0.05) was also shown in the CPRS depression sub-scale at the end of the study. No significant between-group differences were found in the incidence of extrapyramidal side-effects at week 20, though consumption of the antiparkinsonian medication orphenadrine was significantly higher (p. less than 0.05) in the fluphenazine decanoate group (mean dose 102 mg) compared to a mean dose of 58 mg for the haloperidol decanoate group. More patients on fluphenazine decanoate gained weight than patients on haloperidol decanoate, but the difference was not statistically significant.

Adult↗

PubMedDate not supplied

The influence of gabaergic system on cataleptogenic action of analgesics and haloperidol.

The effect of agonists and antagonists of the gabaergic system on catalepsy induced by morphine, fentanyl and haloperidol was investigated in the rat. The compounds inhibiting gabaergic neurotransmission, bicuculline and picrotoxin, given in subconvulsive doses (0.1-0.5 mg/kg) in general do not evidently affect cataleptogenic effects of the analgesics and haloperidol. Of the gabaergic agonists muscimol (0.2-0.5 mg/kg) potentiates only the haloperidol catalepsy, without changing the action of analgesics. Aminooxyacetic acid (AOAA, 25 mg/kg) markedly potentiated the catalepsy brought about by analgesics, while weakly and insignificantly facilitated that induced by haloperidol. Baclofen in a low dose (1 mg/kg) antagonized the action of haloperidol and fentanyl, whereas in higher doses (2-8 mg/kg) it did not visibly affect the action of any investigated drugs. Thus the action of gabaergic agonists and antagonists on the analgesic and haloperidol catalepsy varies, depending on the dose and kind of the agent affecting the gabaergic system.

Aminooxyacetic Acid↗

PubMed1986

Plasma haloperidol levels drawn at neuroleptic threshold doses: a pilot study.

The daily haloperidol doses of 33 newly admitted, acutely psychotic schizophrenic patients were rapidly adjusted to a point at which slight hypokinesia-rigidity first appeared on clinical examination (the neuroleptic threshold). The mean daily haloperidol dose at which the neuroleptic threshold was crossed was 4.2 +/- 2.4 mg/day. The plasma haloperidol levels obtained at these neuroleptic threshold doses clustered around a mean of 4.9 +/- 2.9 ng/ml. This plasma haloperidol level distribution extensively overlaps the proposed lower boundaries for the therapeutically effective range of plasma haloperidol levels, but it is below the range in which coarse extrapyramidal side effects appear in high frequency (greater than 10 ng/ml). Sixty-seven percent of our patients demonstrated moderate or greater therapeutic improvement within 3 weeks of treatment at neuroleptic threshold doses, a therapeutic efficacy rate identical to that expected with standard neuroleptic doses. The authors propose that the neuroleptic threshold is a readily available clinical marker which identifies a range of plasma haloperidol levels capable of producing therapeutic response with minimal associated coarse extrapyramidal side effects.

Adolescent↗

PubMedDate not supplied

Comparative evaluation of the behavioural consequences of prenatal and early postnatal exposure to haloperidol in rats.

The intensity of apomorphine (1-2 mg/kg)-induced stereotyped behaviour was significantly lower in 60 day old offspring of rats treated with haloperidol during pregnancy (0.5 mg/kg SC for 15 days, beginning on day 4 after conception) than in vehicle-exposed animals. Moreover, at 60 days of age, apomorphine (1-2 mg/kg)-induced inhibition of locomotor activity was much less marked in haloperidol-pretreated than in vehicle-pretreated rats. Conversely, our previous data showed that behavioural supersensitivity to apomorphine (1-2 mg/kg) was still present 40 days after the last administration of haloperidol, if the animals received the drug (0.5 mg/kg SC) from birth to 20 days of age. Finally, at 80 days of age, animals prenatally exposed to haloperidol were subjected to a differential reinforcement of low rates schedule (DRL-15 sec). The results indicate that the acquisition of the DRL task performance criterion (Rs/Rf less than or equal to 2.5) was significantly more rapid in control animals than in haloperidol-pretreated rats. In this regard, we previously showed that early postnatal exposure to the neuroleptic also impairs the acquisition of the DRL schedule in adult rats. These data confirm and extend the differences in behavioural consequences of prenatal and early postnatal exposure to haloperidol, and further point to the usefulness of DRL task in the evaluation of subtle behavioural changes induced by psychotropic drugs in the absence of overt signs of neurotoxicity.

Animals↗

PubMed1982

Activation of retinal tyrosine hydroxylase: tolerance induced by chronic treatment with haloperidol does not modify response to light.

A single dose of haloperidol administered to rats in the dark increases the activity of retinal tyrosine hydroxylase. The ability of haloperidol to activate the enzyme is diminished 24 hr after terminating 22 to 30 days of treatment with haloperidol. The retinal enzyme is also tolerant to activation by treatment with chlorpromazine. In contrast, exposure of the animals to light activates the enzyme to the same extent in chronic haloperidol-treated and control animals. Thus, chronic haloperidol treatment does not modify the ability of the retinal enzyme system to respond to the physiological stimulus, light. Apparently, activation of retinol tyrosine hydroxylase by haloperidol and light occurs by independent mechanisms.

Animals↗

PubMed1983

A double-blind controlled trial of pipotiazine, haloperidol and placebo in recently-hospitalized acute schizophrenic patients.

Ninety recently-admitted acute schizophrenic patients, aged 18 to 40 years (mean age: 29) were stratified by schizophrenic subgroups, distributed at random among three groups (pipotiazine, haloperidol and placebo), and evaluated for 27 days by the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI). All groups received 20 mg of haloperidol and 50 mg of chlorpromazine im during the first 3 days, followed by wash-out for 2 days and then oral pipotiazine, haloperidol or placebo for the following 21 days. The dosage was adjusted to the clinical response of the patients and the mean dose was 21.4 mg for pipotiazine and 11.5 mg for haloperidol. At the end of the trial on the 27th day there was no significant difference between pipotiazine and haloperidol, but the effect of both active drugs was significantly different from that of the placebo. In the period corresponding to the 6th to 27th day, extrapyramidal side effects (EPS) occurred to the same extent in the pipotiazine and haloperidol groups, with predominance of Parkinsonian reactions, and no EPS were observed in the placebo group. Our data for a Brazilian population confirm the only other double-blind study of these drugs reported in the literature.

Adolescent↗

PubMed1980

A comparison of the cardiovascular effects of haloperidol, thioridazine and chlorpromazine HCl.

Transient hypotension, electrocardiographic conduction changes and cardiac arrhythmias have been reported with the use of certain anti-psychotic agents. To assess these observations, we compared the effects of haloperidol, thioridazine and chlorpromazine HCl on alpha-adrenergic receptors, mean aortic pressure, myocardial contractile force and myocardial electrophysiology in anesthetized dogs. The results from these studies indicated that, on a milligram basis, chlorpromazine HCl was equipotent to haloperidol, and thioridazine was 0.5 times as potent as haloperidol as an alpha-adrenergic receptor blocker and as a myocardial depressant. Each compound induced conduction nonhomogeneity in myocardial conducting tissue. However, as a neuroleptic, when tested in dogs, haloperidol was 50 times more potent than chlorpromazine HCl and 180 times more potent than thioridazine. The therapeutic safety indices (cardiovascular effect dose/neuroleptic dose) for haloperidol regarding alpha-adrenergic blockade, hypotension, myocardial depression and ventricular conduction delay were 4, 145, 235 and 125, respectively, whereas these indices for chlorpromazine and for thioridazine were 0.06, 2, 4, 6 and 0.05, 1, 3 and 1, respectively. Therefore, because of differences in neuroleptic potency, therapeutic doses of haloperidol are less likely to cause adverse cardiovascular effects than are those of either chlorpromazine HCl or thioridazine.

Animals↗

PubMed1984

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

UNLABELLED: 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).

Adult↗

PubMed1983

[High dosage haloperidol reduces cataleptic response with increased noradrenaline metabolism in the rat brain areas].

The neurochemical background of clinical experiences that the patients receiving high dosage haloperidol showed no extrapyramidal side effects was investigated by using rats. Haloperidol at doses of 1, 2.5, 5, 7.5 and 10 mg/kg, ip caused a dose-dependent decrease in the duration of catalepsy. Haloperidol at a dose of 10 mg/kg induced catalepsy lasting only 20% of that by 1 mg/kg. Haloperidol decreased noradrenaline content in the frontal cortex and thalamus in a dose-dependent manner while 3-methoxy-4-hydroxyphenylglycol content showed a dose-dependent increase in the same brain areas. Thus, there is an inverse relationship between the duration of catalepsy and the ratio of 3-methoxy-4-hydroxyphenylglycol to noradrenaline in the frontal cortex or thalamus. In contrast, haloperidol caused a dose-dependent decrease in homovanillic acid and 3, 4-dihydroxyphenylacetic acid content in the striatum and mesolimbic area. These results indicate that noradrenergic hyperfunction in the frontal cortex or thalamus induced by high dosage haloperidol may reduce cataleptogenic effect of the drug via indirect stimulation of dopaminoceptive neuron in the striatum or mesolimbic area.

Animals↗