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PubMed2000

Intramuscular ziprasidone compared with intramuscular haloperidol in the treatment of acute psychosis. Ziprasidone I.M. Study Group.

BACKGROUND: This 7-day, randomized, open-label, multicenter, international study compared the efficacy and tolerability of intramuscular (i.m.) ziprasidone with haloperidol i.m. and the transition from i.m. to oral treatment in hospitalized patients with acute psychotic agitation (related to DSM-III-R diagnoses). METHOD: Patients received up to 3 days of flexible-dose ziprasidone i.m. (N = 90) or haloperidol i.m. (N = 42) followed by oral treatment to day 7. After an initial ziprasidone i.m. dose of 10 mg, subsequent i.m. doses of 5 to 20 mg could be given every 4 to 6 hours (maximum daily dose = 80 mg) if needed, followed by oral ziprasidone, 80-200 mg/day. Haloperidol i.m. doses of 2.5 to 10 mg were given on entry, followed by 2.5 to 10 mg i.m. every 4 to 6 hours (maximum daily dose = 40 mg) if needed, then by oral haloperidol, 10-80 mg/day. RESULTS: The mean reductions in Brief Psychiatric Rating Scale (BPRS) total, BPRS agitation items, and Clinical Global Impressions-Severity scale scores were statistically significantly greater (p < .05, p < .01, and p < .01, respectively) after ziprasidone i.m. treatment compared with haloperidol i.m. treatment. Further reductions in these scores also occurred in both groups following transition to oral treatment. Ziprasidone was associated with a lower incidence of movement disorders and a reduced requirement for anticholinergic medication during both i.m. and oral treatment compared with haloperidol. Movement disorder scale scores improved with ziprasidone i.m. and oral treatment, but deteriorated with haloperidol. Other adverse events were rare with both treatments. CONCLUSION: Ziprasidone i.m. was significantly more effective in reducing the symptoms of acute psychosis and was better tolerated than haloperidol i.m., particularly in movement disorders. The transition from ziprasidone i.m. to oral ziprasidone was effective and well tolerated.

Acute Disease↗
PubMed2003

An integrated analysis of acute treatment-emergent extrapyramidal syndrome in patients with schizophrenia during olanzapine clinical trials: comparisons with placebo, haloperidol, risperidone, or clozapine.

BACKGROUND: The frequency and severity of extrapyramidal syndrome (EPS) were evaluated in patients with DSM-III or DSM-IV schizophrenia in the acute phase (- 8 weeks) of randomized, double-blind, controlled trials from the integrated olanzapine clinical trial database. METHOD: This retrospective analysis included 23 clinical trials and 4611 patients from November 11, 1991, through July 31, 2001. Incidences of dystonic, parkinsonian, and akathisia events were compared using treatment-emergent adverse-event data. Categorical analyses of Simpson-Angus Scale and Barnes Akathisia Scale (BAS) scores, use of anticholinergic medications, and baseline-to-endpoint changes in Simpson-Angus Scale and BAS scores were compared. RESULTS: A significantly smaller percentage of olanzapine-treated patients experienced dystonic events than did haloperidol- (p <.001) or risperidone-treated patients (p =.047). A significantly greater percentage of haloperidol-treated patients experienced parkinsonian (p <.001) and akathisia (p <.001) events than did olanzapine-treated patients. Categorical analysis of Simpson-Angus Scale scores showed significantly more haloperidol- (p <.001) or risperidone-treated patients (p =.004) developed parkinsonism than did olanzapine-treated patients. Olanzapine-treated patients experienced significantly greater reductions in Simpson-Angus Scale scores than did haloperidol- (p <.001), risperidone- (p <.001), or clozapine-treated (p =.032) patients. Categorical analysis of BAS scores showed significantly more haloperidol-treated patients experienced treatment-emergent akathisia versus olanzapine-treated patients (p <.001). Significantly greater reductions in BAS scores were experienced during olanzapine treatment versus placebo (p =.007), haloperidol (p <.001), and risperidone (p =.004) treatments. A significantly smaller percentage of olanzapine-treated patients received anticholinergic medications compared with that of haloperidol- (p <.001) or risperidone-treated patients (p =.018). Compared with that in olanzapine-treated patients, the duration of anticholinergic cotreatment was significantly longer among haloperidol- (p <.001) or risperidone-treated patients (p =.040) and significantly shorter among clozapine-treated patients (p =.021). CONCLUSION: This analysis of available data from olanzapine clinical trials lends additional support to olanzapine's favorable EPS profile.

Acute Disease↗
PubMed2005

Long-term maintenance therapy with quetiapine versus haloperidol decanoate in patients with schizophrenia or schizoaffective disorder.

OBJECTIVE: To compare the long-term efficacy and tolerability of oral quetiapine with those of intramuscular haloperidol. METHOD: Patients with DSM-IV-diagnosed schizophrenia or schizoaffective disorder requiring long-term antipsychotic treatment were randomly assigned to open-label oral quetiapine or intramuscular haloperidol decanoate for 48 weeks. Clinicians were instructed to target dosing at 500 mg/day of quetiapine or 200 mg of haloperidol decanoate every 4 weeks. The Positive and Negative Syndrome Scale was used to assess efficacy; the Simpson-Angus Scale and the Barnes Akathisia Scale were used to assess safety and tolerability. For statistical analyses, a general linear mixed-model repeated-measures analysis of covariance was used, with change scores for dependent variables computed with the baseline score as covariate. Data were collected from 1998 to 2001. RESULTS: Thirty-five patients were enrolled, but 6 did not participate after being informed of their treatment assignment; 4 of the 6 withdrawals were assigned to haloperidol decanoate. Mean doses at week 48 were 493 mg/day of quetiapine (N = 16) and 170 mg/28 days of haloperidol decanoate (N = 9). Survival analysis showed no between-group differences in estimates of the number of patients remaining exacerbation-free over time. Both drugs were efficacious, but quetiapine was significantly better than haloperidol decanoate in controlling negative symptoms (p < .05). The incidence of extrapyramidal symptoms was low in both groups; patients receiving quetiapine showed significantly greater improvement in rigidity and akathisia (p < .05). CONCLUSION: Oral quetiapine was as efficacious as intramuscular haloperidol in preventing symptom exacerbation over 48 weeks in patients with schizophrenia or schizoaffective disorder, with fewer extrapyramidal symptoms, especially rigidity and akathisia. Quetiapine was more efficacious than haloperidol decanoate in treating negative symptoms.

Administration, Oral↗
PubMed1999

A comparison of olanzapine with haloperidol in cannabis-induced psychotic disorder: a double-blind randomized controlled trial.

Little controlled data exist on the treatment of substance induced psychotic disorders. In this study, 30 patients meeting DSM-IV criteria for cannabis induced psychotic disorder were randomly allocated to receive either olanzapine or haloperidol in a 4-week double-blind clinical trial. There were no significant outcome differences between the two groups on any of the primary outcome measures, the Brief Psychiatric Rating Scale (haloperidol 25.7; olanzapine 27.1; P = 0.70); Clinical Global Impression (CGI) severity scale (haloperidol 1.8, olanzapine 2.3; P = 0.21) or the CGI improvement scale (haloperidol 1.3, olanzapine 1.7; P = 0.16). The haloperidol group however, developed significantly more extrapyramidal side-effects as measured by the Simpson Angus Scale (haloperidol 11.4, olanzapine 2.5; P = 0.014). Significantly (P = 0.027) more biperidin was used for extrapyramidal side-effects in the haloperidol (7.143 mg) than in the olanzapine (0.357 mg) group. Olanzapine appears to be as effective as haloperidol in the treatment of cannabis induced psychotic disorder, but is associated with a lower rate of extrapyramidal side-effects.

Adult↗
PubMedDate not supplied

[Economic comparison of olanzapine versus haloperidol in treatment of schizophrenia in France].

PURPOSE: The purpose of this study is to provide an economic comparison of olanzapine-treated and haloperidol-treated patients from the subset of French patients who participated in a large, international, randomised clinical trial in schizophrenia. METHODS: Patients were evaluated from randomisation until discontinuation, drop out or completion of the 52-week study. The primary clinical measure was "clinically important response" (derived from BPRS total scores). The secondary measure was "clinically important improvement" (derived from CGI severity of illness scores). The primary economic measure was mean per diem, per patient total direct medical costs. RESULTS: A total of 275 French patients where included in the study. Demographics and other baseline differences between olanzapine- and haloperidol-treated patients were not statistically significant. Olanzapine-treated patients (205 +/- 142 days) experienced significantly (p < 0.001) longer evaluation periods than haloperidol-treated patients (132 +/- 129 days). Olanzapine-treated patients (54%) were significantly (p = 0.03) more likely to experience a clinically important response than haloperidol-treated patients (40%). Olanzapine-treated patients (69%) were significantly (p = 0.02) more likely to experience clinically important improvement than haloperidol-treated patients (54%). The mean per diem, per patient total direct medical cost was statistically lower (p = 0.033) for olanzapine-treated patients (FF619 +/- 509) compared to haloperidol-treated patients (FF756 +/- 478). CONCLUSION: Olanzapine treatment was associated with significantly better clinical outcomes and per diem total direct medical cost than haloperidol treatment. The findings indicate that olanzapine is dominant compared to haloperidol for the treatment of schizophrenia, in the context of analysed data. These findings produce increased relevance in France to the existing evidence supporting olanzapine's cost and effectiveness profiles.

Adult↗
PubMed1992

Differential effects of haloperidol and clozapine on neurotensin gene transcription in rat neostriatum.

A single dose of typical neuroleptic, haloperidol, has been demonstrated to increase the expression of neurotensin/neuromedin N (NT/N) mRNA in the dorsolateral striatum within 1 hr of its administration (Merchant et al., 1991). The present study further investigated neuroleptic-induced regulation of NT/N gene transcription. Levels of NT/N mRNA were examined at various times following a single dose of haloperidol (1 mg/kg, i.p.) or the atypical antipsychotic clozapine (20, 30, or 40 mg/kg, i.p.) by in situ hybridization histochemistry and quantitative solution hybridization. In the dorsolateral striatum, the two drugs had strikingly different effects; haloperidol rapidly (within 30 min) increased the expression of mature NT/N mRNA while virtually no increase was observed in response to nontoxic doses of clozapine at any of the time points examined. Following haloperidol, maximal induction occurred at 7 hr, at which time NT/N mRNA levels were an order of magnitude higher than basal levels. By 20 hr after haloperidol, there was a significant decline in striatal NT/N mRNA levels. In situ hybridization analysis using an intron-derived probe revealed that haloperidol-induced increases in mature NT/N mRNA levels in the striatum were preceded by a transient increase in intron-containing NT/N gene transcripts. These data strongly indicate that acute haloperidol treatment results in transient transcriptional activation of NT/N gene, although a concomitant effect on the stability of NT/N primary transcripts cannot be ruled out. In contrast to their differential effects in the dorsolateral striatum, a single dose of both haloperidol and clozapine induced a small but significant increase in NT/N mRNA expression in the shell sector of the nucleus accumbens. These results raise the possibility that NT neurons in the nucleus accumbens may, at least in part, mediate the antipsychotic effects of classical neuroleptics, whereas NT cells in the dorsolateral region of the striatum may be involved in mediating other effects of typical neuroleptics such as extrapyramidal motor symptoms.

Animals↗
PubMed1992

Effect of chronic haloperidol treatment on stimulated synaptic overflow of dopamine in the rat striatum.

In vivo voltammetry was used to assess the change in stimulated striatal dopamine overflow in response to various treatments with the dopamine receptor antagonist haloperidol. Dopamine overflow was induced with stimulating electrodes implanted in the medial forebrain bundle of anesthetized rats while dopamine concentrations were monitored with Nafion-coated, carbon-fiber microelectrodes implanted in the striatum. An acute challenge of haloperidol (0.5 mg kg-1, i.p.) given to naive animals caused stimulated overflow to increase at all stimulation frequencies (10-60 Hz), with the greatest change, 5-fold, occurring at 30 Hz. These results have been compared to those obtained in a different group of rats given daily injections of haloperidol (0.5 mg kg-1, s.c.) for 30 consecutive days. On the 30th day, dopamine striatal tissue levels and uptake kinetics were not altered by this treatment, but 3,4-dihydroxyphenylacetic acid tissue levels were elevated almost 2-fold. A challenge dose of haloperidol (0.5 mg kg-1, i.p.) administered to the animals treated with chronic haloperidol did not elicit a change in stimulated dopamine overflow. In two other groups, rats were withdrawn from 30-day haloperidol treatment for 3 days or 14 days before experimentation. Stimulated dopamine overflow concentrations in both groups were not significantly different from naive animals. When the withdrawn animals were given a haloperidol challenge (0.5 mg kg-1, i.p.), 15- and 12-fold increases in overflow for 3-day and 14-day withdrawal groups, respectively, were observed at a stimulation frequency of 30 Hz. Thus, chronic treatment with haloperidol induces long-lasting effects on the capacity of dopamine receptors to modulate dopamine release.

Animals↗
PubMedDate not supplied

[Elimination of haloperidol from erythrocytes surfaces supernatant and blood plasma].

The aim of the study was to investigate the adsorption rate of haloperidol on erythrocytes surfaces. The pharmacokinetic and pharmacodynamic parameters of haloperidol were monitored in the experiment. The neuroleptic was administered to 12 adult dogs and the blood samples were collected for further analysis following 20, 30, 60, 180, 240, 360, 420 and 480 minutes after the injection. The groups of samples (blood plasma and supernatant) were monitored during this period. The differences between haloperidol concentration in the supernatant and blood plasma were compared. Our data have shown that dynamics of the elimination of intact and acidified forms of haloperidol from the supernatant and the blood serum are not the same. Intact and acidified forms are differently regulated by plasma. albumines and globulines. The process of redistribution of haloperidol between the both substrates takes place, while the supernatant has a donor function for the free form of haloperidol and represents the acceptor of the haloperidol's metabolites. This provides the possibility to develop multidiscipline approach to the optimization to the prescription of haloperidol.

Animals↗
PubMed2005

A 4-week, double-blind comparison of olanzapine with haloperidol in the treatment of amphetamine psychosis.

OBJECTIVE: To compare the efficacy and tolerability of olanzapines and haloperidol in treating patients with amphetamine psychosis. MATERIAL AND METHOD: Fifty-eight patients experiencing episode of amphetamine psychosis were randomly assigned to olanzapine (N=29) or haloperidol (N=29) in 1:1 (olanzapine: haloperidol) ratio. All patients started with 5-10 mg/day of the study drug; after each 7-day period, the study drug could be adjusted in 5-mg increments or decrements within the allowed dose range of 5-20 mg/day during the 4-week double-blind period. RESULTS: Clinical response was seen in both treatment groups since the first week. Ninety three percent of the olanzapine patients (N=27 of 29) and 79.3% of the haloperidol patients (N=23 of 27) were clinically improved at endpoint. These differences were not statistically significant (p=0.25). The Simpson-Angus total score change from baseline to endpoint reflected no extrapyramidal symptoms among the olanzapine-treated patients (median=0.0, range=0.0). In contrast, worsening occurred among the haloperidol-treated patients (median=0.2, range=0.0-3.1). The differences of mean change in Simpson Angus Scale significantly favored olanzapine (p<0.01). Change to endpoint on the Barnes Akathisia Scale showed that olanzapine-treated patients' scores were close to the baseline (median=0.0, range=-1.0-0.0), whereas haloperidol-treated patients' scores worsened from the baseline (median=0.0, range=-1.0-3.0). This difference was statistically significant (p=0.02). CONCLUSION: Both olanzapine and haloperidol were efficacious in the treatment of patients with amphetamine psychosis. Olanzapine was superior to conventional neuroleptic haloperidol in treatment safety with lower frequency and severity of extrapyramidal symptoms.

Adult↗
PubMed1990

Atypical neuroleptics in acute schizophrenia: a double-blind comparative study of remoxipride and haloperidol.

In the present double-blind study comprising 6 weeks, remoxipride was compared with haloperidol in acute schizophrenic patients (DSM-III). Symptoms assessment was performed using the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impressions (CGI) and the Present State Examination (PSE). Extrapyramidal Symptoms (EPS) were assessed using the Simpson and Angus scale. Side effects were also recorded both by spontaneous reports and by active questioning. Seventy-one patients entered the study, 36 in the remoxipride group and 35 in the haloperidol group. There were 10 dropouts, 4 in the remoxipride group and 6 patients in the haloperidol group. The PSE profile revealed a similar reduction in the symptom clusters of psychosis in both treatment groups. Forty-seven percent of the patients in the remoxipride group and 34 percent of the patients in the haloperidol group showed clinically relevant improvement (reduction of total BPRS score by 50% or more). Similar results were obtained with the CGI. All EPS except "glabella tap" occurred significantly less frequently in the remoxipride group compared to the haloperidol group. Substantially lower incidence of EPS was found by active questioning in the remoxipride group compared to the haloperidol group. Also, considerably lower incidences of drowsiness/somnolence, tiredness/fatigue, and concentrating difficulty were observed in the remoxipride group. At the end of treatment, 66 percent of the patients in the haloperidol group and 22 percent in the remoxipride group were using anticholinergics. This study indicates that the newly developed neuroleptic remoxlpride is an effective, clinically safe, and well tolerated antipsychotic compound. In particular, few EPS were induced by remoxipride, as compared to haloperidol.

Acute Disease↗
PubMed1987

Behavioral and neurochemical responses to haloperidol and SCH-23390 in rats treated neonatally or as adults with 6-hydroxydopamine.

Behavioral and neurochemical effects of haloperidol (D2-dopamine antagonist) and SCH-23390 (D1-dopamine antagonist) were examined in unlesioned rats and in rats lesioned with 6-hydroxy-dopamine (6-OHDA) as adults or as neonates. In unlesioned rats, chronic haloperidol treatment (15 days) resulted in an increase in D2-dopamine receptor density, as measured with [3H]spiperone, in the nucleus accumbens and in the caudate-putamen. Rats treated as adults with 6-OHDA responded to chronic haloperidol similarly to controls. However, adult rats treated with 6-OHDA as neonates did not exhibit an increase in [3H]spiperone binding in response to chronic haloperidol treatment. Control and adult 6-OHDA-treated rats given haloperidol exhibited a profound akinesia. In contrast, rats that received 6-OHDA as neonates and were tested as adults did not display a significant behavioral response to haloperidol at doses as high as 2 mg/kg. Results similar to those for haloperidol were also found for SCH-23390. Chronic treatment (15 days) with this D1-dopamine antagonist increased [3H]SCH-23390 binding in the nucleus accumbens and caudate-putamen in unlesioned rats as well as in adult 6-OHDA-treated rats. However, after neonatal 6-OHDA treatment, an elevation in [3H]SCH-23390 binding did not occur after chronic SCH-23390 treatment. SCH-23390 produced akinesia similar to that produced by haloperidol in unlesioned and in adult 6-OHDA-treated rats. In contrast, rats lesioned with 6-OHDA as neonates and tested as adults did not exhibit a significant behavioral response to SCH-23390 under our test conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1986

Disposition and metabolism of [14C]-haloperidol in rats.

Absorption, distribution, excretion and metabolism of [14C]-haloperidol in rats were studied after administration of 5 mg/kg. After oral and intramuscular administration, plasma levels of [14C]-haloperidol radioactivity reached the maximum at 1 h and decreased biphasically. The biphasic elimination was also observed after intravenous administration. The area under plasma level-time curve (AUC) from 0 to 24 h after intramuscular and oral administration was 110 and 87% of AUC after intravenous route, respectively. After intramuscular administration, levels of radioactivity in all tissues examined were higher than plasma and blood levels at 1 h. The lung, Harderian gland, pancreas, kidney, liver, spleen and adrenal had higher levels than other tissues. Most of tissue levels decreased virtually with similar half lives to plasma level and lowered to less than 1 microgram eq/g at 48 h, when negligible recoveries were found in most tissues. Findings concerning distribution obtained by whole-body autoradiography essentially agreed with those by above radiometry. Levels in the placenta and fetus in the pregnant rat were similar to each other and obviously higher than maternal blood level at 1 h after intramuscular administration but no radioactivity was seen in fetus at 48 h. In the lactating rat, milk levels were several times as high as plasma levels and decreased virtually in parallel with plasma levels after intramuscular administration of [14C]-haloperidol. Within 96 h after intramuscular administration, about 99% of administered radioactivity was excreted in urine (about 46%) and feces (about 53%), respectively. About 54% of radioactivity was excreted in the rat bile within 48 h after intramuscular administration. Administration of the bile obtained and thus containing [14C]-haloperidol radioactivity into the duodenum revealed that partial enterohepatic circulation occurred. After intramuscular administration, plasma contained p-fluorobenzoylpropionic acid and p-fluorophenylaceturic acid with comparable concentrations to unchanged haloperidol. Haloperidol alone could be detected in the brain. The liver, kidney, lung and submaxillary gland were also analyzed for their metabolites. Their metabolite compositions differed from each other. Unchanged haloperidol concentration was much higher in all tissues examined than that in plasma. The major urinary and biliary metabolite was p-fluorophenylaceturic acid and conjugates (glucuronide and sulfate) of haloperidol, respectively.

Animals↗
PubMed1985

Differential effects of haloperidol decanoate, a long-acting neuroleptic, in behavioral and biochemical tests.

The pharmacological activities of haloperidol decanoate in several behavioral and biochemical tests for neuroleptics were pursued to validate its clinical mode of action. Haloperidol decanoate itself was about 40 times less potent than haloperidol in inhibiting 3H-spiperone binding to rat striatum in vitro and its direct application into the cerebral ventricle of mice showed no effect on brain concentrations of dopamine metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC). When injected intramuscularly, haloperidol decanoate exhibited various behavioral and biochemical effects together with prolonged accumulation of the parent drug haloperidol in dopamine-rich areas of the brain, but there was a clear difference in the time-course patterns of the effects. Conditioned avoidance responses in mice and rats were suppressed for a long period of days in the time-course pattern parallel to the elevation of brain haloperidol levels; the effect reached the peak a couple of days after the treatment and remained there over a week with gradual recovery towards 1 month after the injection. On the other hand, tolerance developed as rapidly as within 7 days to the antagonistic effects on apomorphine-induced stereotyped behaviours in mice and rats and to prolactin-releasing activity in rats. Biochemically, there was a regional difference in the brain in the time-course of effect of haloperidol decanoate. Namely, the initial increase in dopamine metabolites was no longer seen in the striatum on day 21, whereas it still persisted in the frontal cortex. Thus, the present study has confirmed on the one hand the assumption that haloperidol decanoate is a pro-drug which itself has no neuroleptic activity and validated on the other hand the clinical results that it exhibits long-lasting antipsychotic activities with minimum and tolerable extrapyramidal and prolactin-related side effects.

Animals↗
PubMed1981

The haloperidol effect on the histofluorescence in the caudate nucleus of the rat brain treated with agonistic and antagonistic acetylcholine compounds.

The aim of the paper was to trace the haloperidol effect in the acute and chronic experiments on the histofluorescence in the caudate nucleus of the rat and in conditions of pretreatment of those animals with agonistic and antagonistic compounds of acetylcholine. The experiments were performed on 35 Wistar rats of 180 g mean body weight. According to the experimental model the following were administered: alpha-MT; alpha-MT + haloperidol; Haloperidol in single dose and in repeated multiple doses; Atropine: Atropine + haloperidol; carbachol and carbachol + haloperidol. The Falck et al. [5] histofluorescence method was applied to demonstrate catecholaminergic structures. Changes in the fluorescence of nucleus caudatus of the rat after single or repeated administration of haloperidol and after combinations with cholinergic compounds were always accompanied by the decrease of histofluorescence. We assume that it can be accounted for the existence of functional bonds between the dopaminergic and the cholinergic systems. Those bonds can be explained on the structural grounds, that is by a dense network of nerve endings and in bundles of preterminal nerve fibres. Neurocytes bodies were not sensitive to the administered drugs. The dense network of nerve endings proved to be most sensitive to the action of haloperidol given by itself and in combination with other drugs. A single large dose of haloperidol produced more pronounced effects than several repeated doses of that neuroleptic.

Animals↗
PubMed1994

Effects of chronic haloperidol and clozapine treatment on neurotensin and c-fos mRNA in rat neostriatal subregions.

Previous studies have shown elevation of neurotensin neuromedin N (NT/N) and c-fos mRNA in the dorsolateral region of the rat neostriatum (DLSt) by acute administration of only typical antipsychotic drugs. However, NT/N mRNA in the nucleus accumbens-shell is enhanced acutely by several clinically efficacious antipsychotic drugs, regardless of their motor side effect liability. In the present study, induction of NT/N mRNA in the DLSt was observed again after 28 days of continuous administration (via osmotic minipumps) of haloperidol, but not clozapine. However, this response was only about 50% of that caused by acute haloperidol and c-fos mRNA levels in the DLSt were not elevated after the chronic treatment. An acute challenge of haloperidol 24 hr after chronic haloperidol treatment did not affect the tolerant response of NT neurons but caused a small increase in c-fos mRNA in the DLSt. Similar to the DLSt, chronic haloperidol (but not clozapine) significantly enhanced NT/N gene expression in the ventrolateral striatum, a region thought to be involved in abnormal oral movements, perhaps related to tardive dyskinesia. Interestingly, dopamine D2 receptor binding using [125I]iodosulpride nearly doubled in all regions of the striatum after chronic haloperidol but not clozapine. In contrast to the lateral neostriatum, NT/N mRNA expression in the nucleus accumbens-shell was elevated similarly by chronic treatment with haloperidol and clozapine to a level observed after acute haloperidol treatment. These results demonstrate further that region-specificity of NT/N mRNA regulation discriminate between typical and atypical antipsychotic drugs.

Animals↗
PubMed1996

A comparison of an atypical and typical antipsychotic, zotepine versus haloperidol in patients with acute exacerbation of schizophrenia: a parallel-group double-blind trial.

The atypical antipsychotic zotepine was compared to haloperidol in 126 patients suffering from acute exacerbation of schizophrenia (DSM-III-R) in a randomized, double-blind study. After 8-weeks, 150 to 300 mg zotepine improved scores on the Brief Psychiatric Rating Scale (BPRS) more than 10 to 20 mg haloperidol (-17.03 versus -13.45; 95%CI for zotepine-haloperidol -9.34/2.04). BPRS subscores and Clinical Global impressions (CGI) Severity and improvement subscales showed comparable gains, but scores on the Scale for the Assessment of Negative Symptoms (SANS) improved significantly more with zotepine (-23.82) than haloperidol (-15.15; P < .05; 95%CI for zotepine haloperidol -18.03/-0.18). Adverse events were reported by 71 percent of zotepine and 78 percent of haloperidol patients. Extrapyramidal side effect (EPMS) scores decreased with zotepine (-0.34) but increased with haloperidol (+2.32; P < .05). Seven haloperidol patients reported akathisia but no zotepine patients did (p < .05). Uric acid reductions (which appear to have no clinical consequence) and transient raised liver enzymes were recorded with zotepine. Weight increased on zotepine (2.32 kg; P < .001) and a small increase in pulse rate occurred (P < .05). Both drugs were effective in reducing positive symptoms of schizophrenia; zotepine was significantly more effective against negative symptoms and reduced EPMS.

Adult↗
PubMed1996

Subtype-selective inhibition of N-methyl-D-aspartate receptors by haloperidol.

Previous studies indicate that haloperidol, a therapeutically useful antipsychotic drug, inhibits neuronal N-methyl-D-aspartate (NMDA) responses and has neuroprotective effects against NMDA-induced brain injury. To further characterize this inhibition, we used electrical recordings to assay the effects of haloperidol on four diheteromeric subunit combinations of cloned rat NMDA receptors expressed in Xenopus laevis oocytes: NR1A coexpressed with NR2A, NR2B, NR2C, or NR2D. Haloperidol selectively blocks NR1A/2B subunit combinations (IC50 = approximately 3 microM; maximum inhibition, approximately 85%), whereas the other subunit combinations are > or = 100-fold less sensitive (IC50 = >300 microM). Inhibition of NR1A/2B receptors is insurmountable with respect to glutamate and glycine and does not exhibit voltage dependence. The splice variant combinations NR1B/2B and NR1e/2B are also blocked by haloperidol. In oocytes from some frogs, 30-100 microM haloperidol induces potentiation of NR1A/2A receptor responses. NMDA responses in E16-17 rat cortical neurons cultured for < or = 10 days are inhibited by haloperidol at the same potency and to the extent as NR1/2B receptors (IC50 = approximately 2 microM; maximum inhibition, approximately 80%). In contrast, cells cultured for longer periods show a wide range of sensitivity. This change in pharmacology coincides with a developmental switch in subunit expression; from NR1 expressed with NR2B to NR1 coexpressed with NR2A and NR2B. Inhibition of macroscopic neuronal NMDA responses is mechanistically similar to inhibition of NR1A/2B receptors. Single-channel recordings from neurons show that antagonism is associated with a decrease in the frequency of channel openings and a shortening of mean channel open time. Collectively, our experiments indicate that haloperidol selectively inhibits NMDA receptors comprised of NR1 and NR2B subunits. Inhibition is consistent with action at a noncompetitive allosteric site that is distinct from the glutamate-, glycine-, and phencyclidine-binding sites and is probably mechanistically related to the atypical antagonist ifenprodil. Our results suggest that haloperidol can be used as a tool for investigating NMDA receptor subunit composition and can serve as a structural lead for designing novel subtype-selective NMDA receptor ligands.

Animals↗
PubMed2003

Effect of co administration of haloperidol and large neutral amino acids (tryptophan and valine) on rats striatal dopamine, serotonin and their metabolism.

Haloperidol is a high potency typical neuroleptic used in the treatment of schizophrenia. Administration of haloperidol produces muscles related side effects commonly known as extrapyramidal effects (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. Development of antipsychotics with little/no EPS and/or other side effects is one of the exploring fields of drug research. 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 is, therefore, designed to determine the effect of serotonin precursor tryptophan and a large neutral amino acid (valine) other than tryptophan on the modulation of neurochemical changes in the striatum. Neurochemical estimation were done by HPLC-EC. Present study showed that administration of tryptophan increased tryptophan, 5HT, 5HIAA and DA concentration in the striatum. DOPAC and HVA were not effected. Administration of valine increased DOPAC concentration in the striatum and did not alter tryptophan, 5HT, 5HIAA, DA and HVA concentration. Administration of the haloperidol increased HVA, 5HT and 5HIAA concentration. No effect was produced on tryptophan, DOPAC and DA levels. Valine administration followed by haloperidol injection did not alter striatal tryptophan, 5HT, DA, DOPAC and HVA concentration but decreased 5HIAA concentration. Administration of tryptophan followed by haloperidol injection increased tryptophan and 5HT concentrations and decreased DA levels. No effect was produced on 5HIAA, DOPAC and HVA concentrations. Administration of TRP increased plasma and brain concentration as well as DA levels in the striatum. Administration of valine did not decrease striatal TRP concentration while Haloperidol increased striatal 5-HT and 5-HIAA concentrations and no change in DA levels after haloperidol administration. whereas prior injection of TRP that increased 5HT concentration did not alter haloperidol-induced DA turnover in the brain.

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