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PubMed1983

Simultaneous determination of haloperidol and its reduced metabolite in serum and plasma by isocratic liquid chromatography with electrochemical detection.

We describe a liquid-chromatographic method for simultaneous quantification of haloperidol and its reduced metabolite in plasma and serum. Haloperidol and reduced haloperidol are concentrated from blood samples by liquid/liquid extraction into a hexane/isoamyl alcohol mixture, with chlorohaloperidol as the internal standard. For chromatographic separation we used a reversed-phase cyano-bonded column and a mobile phase of pH 6.8 phosphate buffer/acetonitrile (55/45 by vol). Haloperidol and its reduced metabolite are detected electrochemically at +0.90 V potential between the working and reference electrodes. As little as 0.5 ng per injection is detectable. Within- and between-day CVs for determinations of haloperidol and reduced haloperidol ranged from 4 to 7% each at a concentration of 10 micrograms/L. Haloperidol concentrations measured by this method correlated well with those by gas-chromatography with nitrogen-sensitive detector and by radioimmunoassay. The present method can be used to study the effects of haloperidol on the central nervous system. It is simple enough for use in clinical laboratories that are monitoring haloperidol concentrations in the blood of psychiatric patients.

Antiparkinson Agents↗
PubMed1993

Acute administration of haloperidol enhances dopaminergic transmission.

It has been demonstrated that haloperidol, by blocking presynaptic D2 receptors, enhances dopamine release. However, it is generally assumed that augmentation of dopaminergic transmission is precluded by haloperidol's postsynaptic actions. This assumption was assessed in the present experiment by testing the effects of acute haloperidol administration on the activity of the striatum. Somatosensory stimulation was used to evoke striatal field potentials in rats anesthetized with either urethane or sodium pentobarbital. Haloperidol suppressed striatal responses in a dose-dependent fashion. Enhanced dopaminergic activity, caused by i.v. cocaine or substantia nigra stimulation, similarly suppressed striatal responses. Rather than blocking the effects of cocaine in the striatum, coadministration of haloperidol was additive, causing increased suppression. Substantia nigra lesions that depleted striatal dopamine blocked the suppressive effects of haloperidol. Administration of R-(+)-8-chloro-2,3,4,5-tetrahydro-3- methyl-5-phenyl-1H-3-benzazepine-7-ol to prevent postsynaptic actions of dopamine mediated by D1 receptors did not attenuate haloperidol-induced suppression. The present data suggest that acute administration of haloperidol actually augments dopaminergic activity due to relatively strong presynaptic actions and relatively weak postsynaptic blocking effects. It is plausible that this initial increase in dopaminergic transmission may participate in producing the neural changes evoked by chronic haloperidol administration that allow this drug to have antipsychotic potency.

Animals↗
PubMed1993

Oxidative stress and thiol modification induced by chronic administration of haloperidol.

Haloperidol, a widely used neuroleptic, acts through blockade of dopamine receptors leading to increased turnover of dopamine. Increased turnover of dopamine could lead to excessive production of hydrogen peroxide and, thus, generate oxidative stress. The effect of chronic administration of haloperidol on glutathione (GSH)-protein thiol homeostasis and lipid peroxidation was examined in rat brain regions. The oxidized GSH levels increased significantly, though not substantially, in cortex (CT, 15%), striatum (ST, 28%) and midbrain (MB, 27%). Maximal decreases in GSH levels were noted in CT (23%), ST (28%) and MB (20%) after 1 month of haloperidol administration. The GSH levels recovered thereafter, and after 6 months of haloperidol treatment, the GSH levels were not significantly different from control in ST and MB. The depleted GSH was recovered essentially as protein-GSH mixed disulfide with a concomitant decrease in the protein thiol concentration in all the three regions of the brain. The increase in oxidized GSH concentration represented only 1.8, 2.0 and 3.5% of the depleted GSH in the CT, ST and MB after 1 month of haloperidol administration. The concentration of thiobarbituric acid-reactive products increased significantly up to 3 months of haloperidol treatment, but at the end of 6 months, the levels were substantially decreased. The present study demonstrates that haloperidol administration for 1 month results in significant oxidative stress in CT, ST and MB regions of the brain, as demonstrated by alterations in GSH-protein thiol homeostasis and increased lipid peroxidation products. However, after prolonged administration of haloperidol for 6 months, the GSH-protein thiol homeostasis is restored to a large extent, concomitant with the decrease in the concentration of lipid peroxidation products. Administration of haloperidol leads to development of tolerance (supersensitivity of the dopamine autoreceptors) to neuroleptics, which is associated with decreased turnover of dopamine; this may result in overcoming the oxidative stress generated initially due to increased dopamine turnover.

Animals↗
PubMedDate not supplied

[Erythrocyte ketone reductase activity, total plasma haloperidol and acute psychoses].

Haloperidol (HAL) is a widely used and clinically effective neuroleptic. Its metabolism differs in various animal species. In humans, reduced haloperidol (RHAL), a hydroxy metabolite of HAL, is produced by a cytosolic ketone reductase. Interconversion is known to occur whereby HAL is found in the plasma after administration of RHAL in vivo. Interconversion of HAL and RHAL has been observed in man. However, the capacity for reductive HAL is greater than its oxidation back from RHAL. RHAL, the resulting metabolite of HAL, is reported to be about 10-25% as active as HAL in an animal model. Large intersubject variation has been observed in the pharmacokinetics of HAL and RHAL. A wide variation in reductive drug-metabolizing has been observed in schizophrenic patients treated with HAL. Both high and low RHAL/HAL ratios or RHAL levels were reported to be linked to poor response in HAL-treated patients and might be correlated with the therapeutic window effect of HAL treatment. It is conceivable, therefore, that subjects with high reductive capacity relative to oxidative capacity may have less therapeutic response from the same dose of HAL than those with a low reductive capacity relative to oxidative capacity. This aim of this study was to investigate the HAL reduction among a sample of HAL-treated schizophrenic patients. Because ketone reductases are generally not tissue specific, we investigate the reductase activity in Red blood cells (as described by Inaba), before and during the treatment. Steady-state plasma drug levels during 2 weeks of treatment were quantified. We examined the relationships between fixed doses of HAL treatment, Red blood cells ketone reductase activity, plasma HAL and RHAL levels and the percentage of change of the Positive and Negative Syndrome Scale for Schizophrenia. The participants in this study were 15 inpatients consecutively being treated in the adult psychiatric wards of the University of Lille. All subjects met DSM III-R criteria for schizophrenia (paranoid form). Upon induction subjects were evaluated clinically by trained raters using the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). Subjects were required to score 40 or higher on the general psychopathology subscale of the PANSS to continue participation. All subjects were drug free. Haloperidol was administered orally at three times daily dose. Patients were randomized to treatment at three orally fixed doses: 6 mg per day, 10 mg per day and 15 mg per day. Patients were treated for 2 periods of one week. At the end of each period, dosages could be modified according to the clinic evolution of the patient. PANSS was repeated by the same raters blinded to the haloperidol dosage, plasma concentration and Rbc haloperidol ketone reductase activity, at the beginning and at the end of each period. Blood samples were collected on the same day that clinical assessment were made. Multiple regression analysis (forward stepwise) revealed that Red blood cells reductase activity at D0 is an important variable predicting haloperidol plasma levels at week 2. Similarly Red blood cells reductase activity at D0 and D7 predicted Reduced haloperidol plasma concentrations at week 2. In this sample, no parameter was found to be consistency predicted the percentage change in the PANSS positive subscale from baseline, at week 2. Nevertheless, Red blood cells reductase activity at D0, Reduced haloperidol/haloperidol ratio at week 2, haloperidol plasma levels at week 2 and the dose of haloperidol at week 1 were important variables predicting the percentage change in the PANSS general subscale from baseline at week 2. These results suggest that the knowledge of reductase activity could predict the treatment response in acute schizophrenic patients.

Acute Disease↗
PubMed2001

Behavioral effects of 8-OH-DPAT in single and repeated haloperidol injected rats.

Haloperidol is an antipsychotic drug and shown to be antagonist at D2 receptors and found to cause severe impairment of locomotor performance. The serotonin (5HT1A) receptor agonist 8-OH-DPAT has been reported to attenuate extrapyramidal side effects of haloperidol. The present study was designed to examine the modulatory effect of serotonergic activities on haloperidol induced up-regulation of dopamine D2 receptors. In the acute phase of study, 8-OH-DPAT (0.5 mg/kg/ml) elicited behavioral syndrome was monitored in rats preinjected with haloperidol(5 mg/kg/ml). Results of single haloperidol administration revealed that 8-OH-DPAT induced forepaw treading (p < 0.05) and hyperlocomotion (p < 0.01) were smaller in haloperidol than saline preinjected rats. In repeated phase of study, 8-OH-DPAT (0.5 mg/kg/ml) induced behavioral syndrome was monitored in rats injected with haloperidol for 10 days (x2). The result of repeated haloperidol administration showed that 8-OH-DPAT elicited flat body posture (p < 0.01) was greater in repeated haloperidol injected rats than repeatedly saline injected rats. Relationship between 5HT1A receptors and D2 receptors has been discussed. It is suggested that combining neuroleptics with 5HT1A ligands is thought to improve the preclinical profile of neuroleptics and may be of interest in the development of new compounds that have greater therapeutic potential and/or better tolerated.

Journal Article↗
PubMed1984

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

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

Adult↗
PubMed1999

Nitric oxide, superoxide, and hydrogen peroxide production in brain mitochondria after haloperidol treatment.

Inhibition of mitochondrial respiration and free radical induction have been suggested to be involved in haloperidol neurotoxicity. In this study, mice were injected i.p. with haloperidol, according to two different treatments: (a) a single injection (1 mg/kg), sacrificed 1 h after the injection (single-dose model); and (b) two injections (1 mg/kg each), sacrificed 24 h after the first dose (double-dose model). Determinations of oxygen consumption and hydrogen peroxide (H2O2) production rate were carried out in isolated brain mitochondria. Nitric oxide (NO) and superoxide (O2-) production rates were measured in submitochondrial particles (SMP). Single-dose haloperidol treatment produced a 33% inhibition in malate-glutamate-dependent respiration, while no significant changes were found after double-dose treatment. NO production was inhibited by 39 and 54% in SMP from haloperidol-treated mice (single- and double-dose treatments, respectively) (control value: 1.6 +/- 0.2 nmol/min mg protein). NO steady-state concentration was estimated at about 16.5 nM and was decreased by 40% by haloperidol treatment. Increases of 105 and 54% were found in succinate-supported O2- and H2O2 production rates, respectively, after haloperidol single-dose treatment. Haloperidol treatment generated a 248% increase in SMP O2- production rate when measured in the presence of NADH plus rotenone. Our results suggest that haloperidol neurotoxicity would be mediated by a decreased mitochondrial NO production, a decreased intramitochondrial NO steady-state concentration, and by an inhibition of mitochondrial electron transfer with enhancement of O2- and H2O2 production. This inhibition does not seem to be caused by increased NO or ONOO- formation.

Animals↗
PubMed2001

In vivo canine model comparison of cardiohemodynamic and electrophysiological effects of a new antipsychotic drug aripiprazole (OPC-14597) to haloperidol.

The cardiovascular effects of aripiprazole were assessed in comparison with those of haloperidol using a halothane-anesthetized canine model with monophasic action potential monitoring. Aripiprazole (n = 6) or haloperidol (n = 6) was infused over 10 min at escalating doses of 0.03, 0.3, and 3.0 mg/kg with intervals of 20 min between doses. Clinically relevant plasma concentrations were obtained after 0.03-0.3 mg/kg of aripiprazole as well as haloperidol. After 0.03-0.3 mg/kg of aripiprazole, positive chronotropic, inotropic, and dromotropic effects, shortening of the ventricular effective refractory period (ERP) and repolarization phase, and decrease of total peripheral resistance were observed in a dose-related manner. However, in the presence of a beta-blocking dose of esmolol (0.1 mg/kg/min), these changes were not induced. After 3.0 mg/kg of aripiprazole administration, cardiac effects induced by the lower doses were attenuated or disappeared, while the negative chronotropic, dromotropic, and hypotensive actions and prolongation of ERP and repolarization phase were induced. After 0.03 mg/kg of haloperidol, no significant change was observed, except for the decrease of the peripheral resistance. After 0.3-3.0 mg/kg of haloperidol, negative chronotropic, inotropic, and hypotensive actions, intraventricular conduction delay, and prolongation of ventricular ERP and repolarization phase were observed in a dose-related manner accompanied by further decrease of the peripheral resistance. The inhibitory effects of aripiprazole on cardiovascular parameters in dogs were less potent than those of haloperidol at clinically relevant exposures, moreover, aripiprazole, unlike haloperidol, neither induced early afterdepolarization nor prolonged the ventricular electrical vulnerable period. Therefore, aripiprazole can be considered safer to use than haloperidol.

Animals↗
PubMed1988

Conditioned tolerance to haloperidol- and droperidol-induced catalepsy.

The possible mechanisms of conditioned tolerance to the cataleptogenic effects of haloperidol and droperidol were studied in order to discriminate between "classical" and "conditioned" tolerance. Rats were conditioned by repeated administration (19-27 times) of haloperidol (1.5 mg/kg i.p.) or droperidol (1.5 mg/kg i.p.), respectively, in the presence of a sum of defined environmental (auditory, olfactory and tactile) stimuli. The animals were compared with pseudoconditioned rats, which underwent the same number of drug injections and exposures to the environmental stimuli, but neither were associated. In part of the experiments, one further group of rats was repeatedly treated with only solvent in the presence of the environmental stimuli. Rats conditioned with haloperidol or droperidol showed tolerance to the cataleptogenic effect of a test dose of haloperidol (1.5 mg/kg i.p.) or droperidol (1.5 mg/kg i.p.), respectively, when they were tested in presence of the defined conditioning stimuli. The rats conditioned with droperidol showed significantly less catalepsy than the pseudoconditioned animals 30 min after droperidol administration, whereas in rats conditioned with haloperidol, the catalepsy was less pronounced no sooner than 120 min after haloperidol administration. This was a manifestation of conditioned tolerance. In rats pseudoconditioned with droperidol, the catalepsy was similar to that produced by the drug in drug-naive rats, suggesting no classical tolerance due to repeated administration of the neuroleptic drug. The dopamine turnover in striatum or nucleus accumbens after administration of 1.5 mg/kg of haloperidol i.p. was not altered in rats conditioned with haloperidol when compared with pseudoconditioned animals.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Using ofloxacin as a time marker in hair analysis for monitoring the dosage history of haloperidol.

Hair samples were obtained 1-5 months after ingestion of the antimicrobial ofloxacin, which had been given for 1 or 3 days at the commencement of haloperidol administration, or when its dosage was reduced. The axial distribution of ofloxacin, haloperidol and its active metabolite, reduced haloperidol, was analysed in segments from single strands of hair. Ofloxacin was detected where the content of haloperidol and reduced haloperidol along the hair shaft showed a sharp change, corresponding to the change in dose. When we matched the time scale of the dosage history to the growth rate, which was estimated using ofloxacin as the time marker, the distribution of the haloperidol and reduced haloperidol precisely coincided with the rise and fall in the dose of haloperidol. These findings demonstrate that ofloxacin can serve as a time marker when drug distribution along the hair shaft is used to obtain the drug exposure history of an individual.

Adult↗
PubMed1994

Effect of chronic haloperidol treatment on dopamine-induced inositol phosphate formation in rat brain slices.

The effects of chronic haloperidol administration on the accumulation of inositol phosphates were examined in rat brain slices pre-labeled with [3H]myo-inositol and incubated with various dopaminergic drugs. Rats were treated with haloperidol-decanoate or its vehicle (sesame oil) for two, four or six weeks. Dopamine and the selective D1 agonist, SKF38393, induced a significant increase in lithium-dependent accumulation of [3H]inositol monophosphate (IP1) in the frontal cortex, hippocampus and striatum of vehicle-treated animals, while the selective D2 agonist quinpirole did not show any effect on IP1 accumulation. The actions of dopamine and SKF38393 were blocked by the D1 antagonist, SCH23390, but not by the D2 antagonist, spiperone, in all three brain regions. Haloperidol treatment did not affect basal phosphoinositide turnover in the three brain regions. Four or six weeks of haloperidol treatment significantly decreased dopamine-induced IP1 accumulation in the striatum (by 30% and 25%, respectively), but not in the frontal cortex and the hippocampus. Four weeks of treatment with haloperidol significantly decreased IP1 levels in the striatal slices when measured in the presence of quinpirole. However, the accumulation of IP1 measured in the presence of SKF38393 was not significantly altered after haloperidol treatment. The loss of dopamine-sensitive IP accumulation was not observed in the presence of spiperone after haloperidol treatment. The number, but not the affinity, of [3H]sulpiride binding sites in the striatum was significantly increased (by 34-46%) after chronic haloperidol treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Effects of ceruletide on the dopamine receptor-adenylate cyclase system in striatum and frontal cortex of rats chronically treated with haloperidol.

Chronic treatment of rats with haloperidol decanoate (30 mg/kg and 100 mg/kg IM every 4 weeks for 52 weeks) increased [3H] SCH 23390 binding in striatal membranes by 25% and 50% and in frontal cortical membranes by 56% and 125% in 30 and 100 mg/kg haloperidol treatment groups, respectively. These increases in [3H] SCH 23390 binding to the membranes were restored to control levels after ceruletide treatment (100 micrograms/kg IP twice a day for 5 days). [3H] Spiperone binding to the rat striatal and cortical membranes also increased after chronic haloperidol treatment (by 66% and 99% in striatal membranes and by 27% and 62% in cortical membranes in the 30 and 100 mg/kg haloperidol treatment groups, respectively). Administration of ceruletide to haloperidol-treated rats reduced the increased [3H] spiperone binding to the cortical membranes toward the control level, but ceruletide was not effective in reducing the haloperidol-induced increase of [3H] spiperone binding to the striatal membranes. Activation of adenylate cyclase by dopamine (1 microM or 100 microM) or Gpp(NH)p (1 microM) was reduced in striatal and cortical membranes from haloperidol-treated rats. Ceruletide restored the lowered level of dopamine-stimulated or Gpp(NH)p-stimulated adenylate cyclase activity in the membranes from haloperidol-treated rats to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1990

Double blind comparative study of remoxipride and haloperidol in acute schizophrenic patients.

In the present 6-week double-blind, randomised, multicentre study, the atypical neuroleptic remoxipride was compared to haloperidol in acute schizophrenic patients (DSM-III). Seventy-one patients entered the study, 36 in the remoxipride group and 35 in the haloperidol group. There were ten early withdrawals, four in the remoxipride group and six patients in the haloperidol group. The Present State Examination (PSE) profile revealed a similar reduction in the symptom clusters of psychosis in both treatment groups. Forty-seven per cent of the patients in the remoxipride group and 34% of the patients in the haloperidol group showed clinically relevant improvement (reduction of BPRS total score greater than or equal to 50%). All extrapyramidal symptoms except "glabella tap" occurred significantly less frequently in the remoxipride group as compared to the haloperidol group. Substantially lower incidences of EPS were found by active questioning in the remoxipride group compared to the haloperidol group. In addition, considerably lower incidences were observed in the remoxipride group with respect to drowsiness/somnolence, tiredness/fatigue and concentrating difficulty. At the end of treatment 66% of the patients in the haloperidol group and 22% in the remoxipride group were using anticholinergics. No consistent changes were found in the mean plasma HVA level in either treatment group. In responders (reduction of BPRS total score greater than or equal to 50%) lower baseline HVA levels were observed in both treatment groups. This study indicates that the newly developed neuroleptic remoxipride is an effective antipsychotic compound, which is clinically safe and well tolerated. In particular, few EPS were induced by remoxipride, as compared to haloperidol.

Acute Disease↗
PubMed1995

Haloperidol prevents ethanol-stimulated locomotor activity but fails to block sensitization.

The effect of the dopamine receptor antagonist haloperidol on the development of sensitization to ethanol-induced increases in locomotor activity was examined in DBA/2J mice. In Experiment 1, different groups of mice were given saline or ethanol (2 g/kg) immediately before each of four locomotor activity sessions (48-h intervals), and 1 h after pretreatment with saline, 0.10 or 0.15 mg/kg haloperidol. During a subsequent test, mice showed locomotor sensitization despite blockade of ethanol stimulated activity by haloperidol on the first conditioning trial. Moreover, test session activity was reduced in subjects that had previously received haloperidol, even though haloperidol was not present during testing. The second experiment examined the nature of the latter finding by comparing subjects that received equal exposure to haloperidol but differed in the pairing of its administration with the activity chambers. After four conditioning trials, each group was tested in the absence of haloperidol. Mice that had previously received haloperidol paired with the activity chambers were less active than control groups, suggesting development of a conditioned suppression of activity. Overall, these results suggest a dissociation of the neurobiological mechanisms that mediate the acute locomotor stimulant effects of ethanol and those mediating sensitization. Further, these studies illustrate the importance of antagonist-alone control groups that assess the possible influence of associative learning induced by the antagonist itself.

Animals↗
PubMed1995

GM1 ganglioside administration partially counteracts the morphological changes associated with haloperidol treatment within the dorsal striatum of the rat.

Haloperidol, a typical antipsychotic drug, causes an increase in the mean percentage of synapses within the situation containing a discontinuous, or perforated, postsynaptic density (PSD) following 1 month of treatment (Meshul et al. 1994). This effect is not observed with the atypical antipsychotic drug, clozapine, following subchronic administration (Meshul et al. 1992a). This morphological change is also associated with an increase in the density of dopamine D2 receptors. The synapses containing the perforated PSD are asymmetrical and the nerve terminals contain the neurotransmitter, glutamate, as demonstrated by immunocytochemistry. We have also shown that subchronic treatment with haloperidol (0.5 mg/kg per day, 30 days) results in a decrease in the density of glutamate immunoreactivity within asymmetric nerve terminals associated with perforated and non-perforated PSDs (Meshul and Tan 1994). This could be due to an increase in glutamate release, perhaps due to activation of corticostriatal synapses. Agnati et el. (1983a) reported that administration of GM1 ganglioside blocks the increase in dopamine D2 receptors following haloperidol treatment. GM1 has also been shown to attenuate the release of glutamate (Nicoletti et al. 1989). In order to determine if similar treatment with ganglioside could block the haloperidol-induced ultrastructural changes notes above, rats were co-administered GM1 (10 mg/kg per day) and haloperidol (0.5 mg/kg per day) for 30 days. We report that GM1 blocked the haloperidol-induced increase in striatal asymmetric synapses containing a perforated PSD, but had no effect on the increase in dopamine D2 receptors or the decrease in nerve terminal glutamate immunoreactivity. GM1, either alone or co-administered with haloperidol, also caused a small, but significant, increase in the density of all asymmetric synapses within the striatum. It is possible that the effect of GM1 in attenuating the haloperidol-induced change in glutamate synapses with perforated PSDs is primarily postsynaptic, since GM1 did not block the change in density of glutamate immunoreactivity within asymmetric nerve terminals.

Animals↗
PubMed2003

Fluvoxamine dose-dependent interaction with haloperidol and the effects on negative symptoms in schizophrenia.

Augmentation with low-dose fluvoxamine (50-100 mg/day) to antipsychotic treatment may improve the negative symptoms in schizophrenic patients, but involves a risk of drug-drug interaction. We studied the effects of fluvoxamine on plasma concentrations of haloperidol and reduced haloperidol, and their clinical symptoms, in haloperidol treated patients. Twelve schizophrenic inpatients with prevailingly negative symptoms receiving haloperidol 6 mg/day were additionally treated with incremental doses of fluvoxamine for 6 weeks (25, 75 and 150 mg/day for 2 weeks each). Plasma drug concentrations were monitored together with clinical assessments before and after each phase of the three fluvoxamine doses. Geometric mean of haloperidol concentrations during coadministration of fluvoxamine 25, 75 and 150 mg/day were 120% (95%CI; 114-127%), 139% (95%CI; 130-149%), and 160% (95%CI; 142-178%) of those before fluvoxamine coadministration, respectively. We found positive correlations between increase in plasma haloperidol concentrations and plasma fluvoxamine concentrations. Scores in negative symptoms were significantly reduced after fluvoxamine coadministration, whereas no changes were observed in the other psychiatric symptoms or any subgrouped side effects. Therefore, this study indicates that fluvoxamine increases plasma haloperidol concentrations in a dose-dependent manner. However, relatively small elevations in haloperidol concentration did not lead to the development of extrapyramidal symptoms under the conditions of this study.

Adult↗
PubMed2004

Prolactin levels in male schizophrenic patients treated with risperidone and haloperidol: a double-blind and randomized study.

RATIONALE: There are few data from systematic, double-blind clinical trials that have compared the effect of the typical and the atypical antipsychotics on serum prolactin (PRL) levels in patients with schizophrenia. OBJECTIVES: The goal of this study was to compare the effect of risperidone and haloperidol on serum PRL and investigate the relationship between serum PRL levels and clinical response in patients with schizophrenia. METHODS: Seventy-eight inpatients with a diagnosis of schizophrenia (according to DSM-III-R) were randomly assigned to 12 weeks of treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol after a 2-week washout period, using a randomized, double-blind design. Clinical efficacy was determined using the positive and negative syndrome scale (PANSS). Their serum PRL was assayed by means of radioimmunometric assay (RIA) between pre-treatment and post-treatment, and compared with 30 sex-matched and age-matched normal subjects. RESULTS: Both risperidone and haloperidol treatment significantly increased serum PRL levels in drug-free chronic schizophrenia patients (both P<0.001). Hyperprolactinemia induced by risperidone 6 mg/kg was comparable to levels produced by haloperidol 20 mg/day. Considering dose-adjusted serum PRL levels, risperidone treatment induced a significant elevation of PRL levels compared with haloperidol treatment at the haloperidol equivalent (P<0.001). Change in PRL levels at pre-treatment and post-treatment were related to positive symptom improvement seen in the risperidone group (r=0.51, P=0.016), but not in the haloperidol group (P>0.05). Female patients showed both a higher baseline and post-treatment PRL level and a greater increase in PRL than men (all P<0.05). CONCLUSIONS: Risperidone is associated with a robust effect on prolactin secretion in contrast to the conventional antipsychotic haloperidol. Prolactin monitoring during risperidone treatment should be performed.

Adult↗
PubMed2005

Ziprasidone and haloperidol in the treatment of acute exacerbation of schizophrenia and schizoaffective disorder: comparison of intramuscular and oral formulations in a 6-week, randomized, blinded-assessment study.

RATIONALE: Conventional intramuscular (IM) antipsychotics used in managing acute exacerbation of schizophrenia are associated with side effects such as acute dystonia. OBJECTIVES: To compare the efficacy and tolerability of sequential IM/oral ziprasidone with haloperidol in acute exacerbation of schizophrenia or schizoaffective disorder. METHODS: In a 6-week, multicenter, parallel-group, flexibly dosed study, patients were randomized to ziprasidone (IM up to 3 days, then oral 40-80 mg, b.i.d.) or haloperidol (IM up to 3 days, then oral 5-20 mg/day). Assessments were rater-blinded. RESULTS: At the end of IM treatment, patients receiving ziprasidone (n=427) showed significantly improved Brief Psychiatric Rating Scale Total (BPRS total) scores compared with those receiving haloperidol (n=138) [least-squares (LS) mean change -6.14 for ziprasidone versus -4.13 for haloperidol, P<0.0018]. At endpoint, there were no significant between-group differences in BPRS total scores. There was a significantly greater improvement in BPRS negative subscale scores in ziprasidone-treated patients, both at the end of IM treatment (LS mean change -1.15 for ziprasidone and -0.28 for haloperidol, P<0.0001) and at study endpoint (LS mean change -2.94 for ziprasidone and -2.24 for haloperidol, P<0.0001). Haloperidol-treated patients exhibited significantly greater increases in Extrapyramidal Symptom Rating Scale at end of IM treatment and at endpoint (P<0.0001). They also had significantly higher ratings on the Barnes Akathisia Scale (P<0.0001) and the Movement Disorder Burden Score (P<0.005), as well as higher incidences of movement disorder-related adverse events. CONCLUSIONS: Sequential IM and oral ziprasidone offers important efficacy and tolerability advantages over haloperidol in acute schizophrenia.

Acute Disease↗