Tardive dyskinesia during and following treatment with haloperidol, haloperidol + biperiden, thioridazine, and clozapine.
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The demonstration of a change in adrenergic receptor sensitivity in the central nervous system of mice after withdrawal from long-term treatment with haloperidol.
Mice, administered haloperidol (3 mg/kg/d) in their drinking water for 21 days, displayed, 4 days after cessation of the haloperidol-treatment, marked locomotor stimulation to clonidine (100 or 500 mug/kg) which lasted for about 6 h. 25 mug clonidine/kg was inactive. Premedication with FLA-63 (25 mg/kg) blocked the difference in stimulation after clonidine between the haloperidol- and vehicle-treated animals, but locomotor activity was still present in both groups. Haloperidol-treated animals displayed a supersensitive response to dexamphetamine. The difference in stimulation produced by dexamphetamine in the two groups was completely blocked by phenoxybenzamine (2.5 mg/kg), phentolamine (10 mg/kg), which drugs did not, however, block the locomotor stimulation produced by dexamphetamine in vehicle-treated animals. Pimozide (3 mg/kg) blocked all locomotor stimulation produced by dexamphetamine in both vehicle- and haloperidol-treated groups, while 1 mg/kg completely blocked the dexamphetamine response in vehicle-treated animals but not in haloperidol-treated animals. FLA-63 (25 mg/kg) blocked the difference in response between the haloperidol- and vehicle-treated groups to dexamphetamine, but did not antagonise the stimulation in the vehicle-treated animals. The data suggest that long-term haloperidol treatment leads to the development of "supersensitive" adrenergic receptors in the central nervous system, which, appropriately stimulated, effect an increase in locomotor activity. Moreover, the results indicate that a large component of the supersensitive response to dexamphetamine observed after long-term haloperidol-treatment is due to adrenergic receptor supersensitivity. However, the dopamine receptor (which was shown to be supersensitive to apomorphine) is of fundamental importance because phenoxybenzamine and phentolamine, while blocking the supersensitive response to dexamphetamine, failed to block the response to dexamphetamine in vehicle-treated animals, which was, however, blocked by pimozide.
Adrenergic alpha-Antagonists↗
A comparative study of haloperidol and diazepam in the treatment of anxiety.
In a single-blind study in general practice, 60 patients with anxiety neuroses were randomly allocated to receive either 0.5 mg haloperidol twice daily or 2 mg diazepam 3-times daily for 6 weeks. Eighteen patients (6 on haloperidol and 12 on diazepam) were excluded from the analysis of efficacy. On the Hamilton Rating Scale both haloperidol and diazepam reduced the anxiety and depression scores. The investigator's assessment of 14 anxiety symptoms and signs indicated that haloperidol produced significantly (p=0.05) greater symptomatic improvement than diazepam after 4 and 6 weeks of treatment, and the patients' overall response was also significantly (p less than 0.005) greater with haloperidol. After 6 weeks, 93% of patients felt 'better' or 'much better' on haloperidol, compared with 83% on diazepam. A few, minor side-effects were reported, slightly fewer on haloperidol than on diazepam. In the parameters tested in this study, haloperidol has been shown to be more effective than diazepam in the treatment of anxiety neuroses and appears to provide significantly better overall symptomatic relief and to be more acceptable to patients than diazepam.
Adult↗
The effect of apomorphine and clonidine on locomotor activity in mice after long term treatment with haloperidol.
1. Mice were given haloperidol (approximately 3 mg.kg-1 day-1) or vehicle for 21 days and then withdrawn from the drug. All tests were performed 4 days after withdrawal. 2. Haloperidol treated mice (premedicated with reserpine plus alpha-methyl-p-tyrosine) displayed an increased locomotor response to apomorphine and to apomorphine plus clonidine, but neither haloperidol- or vehicle-treated animals revealed any stimulant response to clonidine. 3. In mice which had not been pretreated with reserpine plus alpha-methyl-p-tyrosine, clonidine produced a significant stimulation of locomotor activity in animals withdrawn from haloperidol but not in those withdrawn from the vehicle. Phenoxybenzamine blocked the locomotor stimulat difference between these two groups, but did not completely antagonized the stimulant effect of clonidine in mice withdrawn from haloperidol. Pimozide was largely effective in blocking the clonidine-induced stimulation. Co-administration of phenoxybenzamine and pimozide was completely effective in blocking the stimulant effect of clonidine in mice withdrawn from haloperidol. 4. The evidence for a change in catecholamine receptor sensitivity was supported compared to the vehicle-treated animals. 5. The data suggest that there is a change in the functional responsiveness of both adrenergic and dopaminergic receptors after withdrawal from long term haloperidol treatment.
Animals↗
The time course of the behavioral effects of amphetamine and their reversal by haloperidol in a primate species.
A group of six marmosets was administered amphetamine (Phase I), amphetamine plus haloperidol (Phase II), and then amphetamine alone (Phase III) over consecutive periods of 27, 51, and 33 days after which drug treatment was terminated (Phase IV). The animals' behavior was monitored during these periods and during a predrug treatment control period. Five mutually exclusive categories of behavior were assessed during the experiment. Social contact between animals was significantly suppressed and inactivity was increased throughout Phases I--III but both measures returned to normal values during Phase IV. Locomotion was significantly decreased towards the end of Phase I and initially during Phase II. Rapid head movements (termed checking) were significantly increased at the beginning of Phase I and again when the haloperidol was withdrawn at the beginning of Phase III. Towards the end of Phase I the animals developed destructive self-grooming habits. The time course of the effects of amphetamine and haloperidol on the different behavioral categories suggests that different mechanisms may be involved in each case. Viewed as a model of schizophrenia, the time course of haloperidol in reversing amphetamine-induced suppression of locomotion most closely resembles the time course of the antipsychotic effect of neuroleptics in man. Some effects of amphetamine (e.g., suppression of social interaction) are not reversed by haloperidol, and some effects of withdrawal of haloperidol (e.g., precipitation of checking movements not present when haloperidol was commenced) do not have an obvious counterpart in the clinical situation.
Amphetamine↗
Cataleptic and anticataleptic effects of muscimol and gabaculine injected into globus pallidus and substantia nigra, and interactions with haloperidol or benzodiazepines.
Intranigral injection of muscimol induced hyperactivity in rats and antagonized haloperidol-induced catalepsy. Intranigral injection of gabaculine, an inhibitor of GABA transaminase, induced similar effects 5h after injection, when the nigral GABA content was increased 7-fold. On the other hand, injections of muscimol (30 ng) into the globus pallidus potentiated the cataleptic effect of haloperidol, and muscimol alone in high doses (100 and 200 ng) induced catalepsy. Gabaculine also induced catalepsy of medium intensity and potentiated the effect of haloperidol 24h after injection, when GABA was increased in the globus pallidus as well as in the substantia nigra. Injections of muscimol into either the globus pallidus or substantia nigra increased striatal HVA and enhanced haloperidol-induced elevation of HVA. Three benzodiazepines, nitrazepam, diazepam and chlordiazepoxide administered orally, potentiated the effect of muscimol (30 ng) injected into the globus pallidus and induced catalepsy. A similar effect was not obtained with phenobarbital. It is suggested that stimulation of GABA receptor or increase of GABA content in the sustantia nigra antagonize haloperidol-induced catalepsy by activation of nigral dopaminergic system, and that enhancement of pallidal GABA function induces catalepsy by non-dopaminergic mechanisms. Potentiation of haloperidol-induced catalepsy by benzodiazepines may be due to enhancement of GABA-ergic transmission within the globus pallidus.
4-Aminobutyrate Transaminase↗
Long-term haloperidol-treatment of mice: a change in beta-adrenergic receptor responsiveness.
Mice administered haloperidol 3 mg/kg/day in their drinking water for 21 days were tested for their locomotor responsiveness to saline or acid vehicle, dl-, l- or d-propranolol, metoprolol, butoxamine or practolol. Haloperidol-treated animals administered saline or acid-vehicle were, in five of six experiments, more active than animals withdrawn from vehicle-treatment. Haloperidol- and vehicle-treated animals responded differently to the non-selective beta-adrenoreceptor antagonists (dl-propranolol and l-propranolol) and selective beta1-adrenoreceptor antagonists (practolol and metoprolol), but not to a selective beta2-adrenoreceptor antagonist (butoxamine). With dl-propranolol (4 mg/kg) the locomotor activity of haloperidol-treated animals was significantly (0.01 less than P less than 0.02) greater than that of the vehicle-treated animals. Similar effects in the same direction were seen with l-propranolol (1 mg/kg, 0.005 less than P less than 0.01), practolol (10 and 100 mg/kg, 0.025 less than P less than 0.05 and 0.01 less than P less than 0.025 respectively) and metoprolol 8 mg/kg, 0.005 less than P less than 0.01). The d-isomer of propranolol which is about 50 times less active as a beta-adrenoreceptor antagonist than the l-isomer, although having equal membrane stabilizing effects, did not differentially affect haloperidol- or vehicle-treated groups. The results suggest that there has been a change in beta 1-adrenoreceptor responsiveness in animals withdrawn from long-term haloperidol treatment.
Adrenergic beta-Antagonists↗
[Acute and chronic effects of carpipramine, clozapine, haloperidol and sulpiride on the metabolism of biogenic amines in the rat brain (author's transl)].
In acute and chronic experiments investigations were made concerning the effect of clozapine, haloperidol, sulpiride and carpipramine on MHPG, HVA and 5-HIAA in rat brain and on motor activity of the animals. The activity of the rats treated with clozapine and haloperidol was reduced on the first day. After 10 days of treatment this effected of clozapine was significantly diminished. The MHPG level increased slightly on the first day of treatment with all four drugs. This elevation was maintained after chronic treatment with carpipramine and sulpiride, whereas clozapine and haloperidol decreased the MHPG content. 5-HIAA values did not show significant changes in acute experiments, whereas in chronic ones there was an increase. Haloperidol and clozapine induced a strong increase of HVA which decreased after 11 days in those animals treated with haloperidol. In comparison to haloperidol, after clozapine application the percentage of HVA-increase was higher in the limbic system than in the nigrostriatum.
Animals↗
A putative multipartite model of haloperidol interaction in apomorphine-disturbed behavior of the dog.
The interaction between various doses of apomorphine and haloperidol on intracranial self-stimulation in the dog was studied using a pradigm in which reinforcing brain-stimulation was controlled by a discriminative auditory stimulus. Reinforced lever-pressing was decreased by low doses of apomorphine and completely suppressed by stereotypogenic doses. At various doses of apomorphine, low doses of haloperidol either increased response inhibition by enhancing stereotypy, or increased lever pressing by reducing stereotypy while concomitantly increasing the number of nonreinforced responses. Intermediate to relatively high doses of haloperidol antagonized stereotypy and the response inhibition produced by apomorphine. High doses of haloperidol antagonized stereotypy but also suppressed self-stimulation. Thus, haloperidol is not only able to restore performance capability, but also disturbed reinforcing and discriminative stimulus control.
Animals↗
Interaction of apomorphine and haloperidol: effects on locomotion and other behaviour in the marmoset.
The behavioural effects of increasing doses of apomorphine and haloperidol were observed in a group of six marmosets. Behaviour was classified quantitatively into categories: Locomotion, inactivity, checking (small head movements), social interaction and purposeful activities. Statistical analysis revealed that apomorphine had a stimulant effect on checking and locomotion which could be antagonized by haloperidol. Activities and social contact were severly reduced by both apomorphine and haloperidol. Inactivity was increased by the lowest dose of apomorphine in otherwise untreated animals. It is suggested that haloperidol antagonizes the stimulant effects of apomorphine but is synergistic to its suppressant effects, and that the low dose effect of apomorphine on inactivity is mediated by a mechanism which may be different from that acted upon by haloperidol.
Animals↗
Catecholamine synthesis in rat brain after axotomy: interaction between apomorphine and haloperidol.
Axotomy of the ascending monoaminergic fibers by means of a complete cerebral hemitransection stimulated the formation of dopa during 30 min after inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCl, 100 mg/kg i.p., in c. striatum and the dopamine-rich part of the limbic system. Apomorphine, 0.5 mg/kg i.p., antagonized the accumulation of dopa not only on the intact but also on the lesioned side. Haloperidol, 2 mg/kg i.p., stimulated dopa accumulation on the intact side but could not further stimulate the increase in dopa caused by transection. When both drugs were given together, the inhibitory effect of apomorphine was fully counteracted by haloperidol on both sides. In the predominantly noradrenaline-innervated occipito-temporal cortex dopa formation was slightly higher on the lesioned than on the intact side and was not markedly influenced by apomorphine. In the rest of the hemispheres the apomorphine-induced decrease in dopa formation was more pronounced on the intact than on the lesioned side and was fully antagonized by haloperidol. The dopamine concentration was slightly higher in the lesioned c. striatum as compared to the intact side irrespective of the drugs administered. In c. striatum and the limbic system haloperidol caused a decrease in dopamine on the intact side which was not antagonized by additional treatment with apomorphine. Hemitransection caused a decrease in noradrenaline especially in the hemisphere portion. Neither apomorphine nor haloperidol or both drugs in combination changed the latter effect. In general, the tyrosine concentration tended to be higher on the lesioned than on the intact side in all brain structures investigated. The data support the view that a local receptor-mediated feedback mechanism exists which is controlling dopamine synthesis even in the absence of impulse flow.
Animals↗
Effects of antipsychotic drugs on action potential production in skeletal muscle. II. Haloperidol: nonspecific and opiate drug receptor mediated effects.
The effects of haloperidol, an antipsychotic butyrophenone, on excitability and action potential production in frog's sartorius muscle fibers were studied. This drug produced a local-anestheticlike effect which developed slowly over 1 to 5 h with lower concentrations (2.7 to 5.3 X 10(-6 M) but was completely reversed by exposing the muscles to a drug-free solution. In studies with intracellular microelectrodes, evidence was obtained showing that haloperidol decreased excitability and depressed action potential production by inhibiting the specific increase in sodium conductance (gNa) which normally follows an adequate stimulus. Evidence also was obtained showing an inhibition of the secondary increase in potassium conductance (gK). Haloperidol is structurally related to meperidine and it was found that the inhibition of gNa produced by haloperidol is partially antagonized by low concentrations of naloxone (2.8 X 10(-8) and 2.8 X 10(-7) M); as was previously shown for meperidine. Thus haloperidol, like meperidine, suppresses action potential production by two mechanisms of action: one, a nonspecific local-anaestheticlike effect; and the other, a specific inhibition of gNa mediated by means of an opiate drug receptor associated with the muscle fiber membrane. Naloxone did not antagonize the effects of chlorpromazine on gNa.
Action Potentials↗
A double blind trial of lithium carbonate and haloperidol in Huntington's chorea.
Six patients with a family history of Huntington's chorea (HC) participated in a double blind crossover trial involving four treatments--lithium carbonate, haloperidol, lithium carbonate and haloperidol, and placebo. Each treatment was administered for three weeks and, at the end of each treatment period, assessments were made of chorea and a number of psychological variables. None of the treatments significantly affected chorea measurements. With regard to the psychological variables, the levels of irritability, the frequency of angry outbursts and depression did appear to be affected in some patients by the treatment. Three patients improved on a combination of lithium carbonate and haloperidol while the remaining three did not. Haloperidol alone significantly raised depression ratings above levels for other treatments including placebo. It is suggested that lithium carbonate and haloperidol together should be seriously considered in the treatment of HC when patients are excessively irritable and impulsive.
Anger↗
Analgesia and haloperidol: a hypothesis.
We have previously reported 10 patient histories involving various intractable pain syndromes where the administration of Haloperidol either eliminated the need for narcotic analgesics or resulted in a significant reduction in narcotic dosage. We are presently undertaking a controlled double-blind evaluation of Haloperidol as an adjunctive treatment for intractable cancer pain. Based upon the reported clinical observations, these findings are discussed from the following aspects: 1. The isomeric similarity of Haloperidol to Meperidine. 2. Dose response between Haloperidol and analgesic effect. 3. The clinical literature regarding the use of Haloperidol for the effective withdrawal or maintenance of narcotic addicts. 4. The analgesic property as it relates to the opiate receptor.
Analgesics↗
Modification of behavioral and neurochemical effects of cocaine by haloperidol.
Cocaine (20 mg/kg, i.p.) stimulated spontaneous motor activity (SMA) and induced stereotypy (ST) in rats. Haloperidol at 0.015 mg/kg, i.p. dose reduced or blocked cocaine-induced ST, but did not affect, drug-induced hyperactivity. At 0.03 mg/kg, i.p. dose of haloperidol, both behavioral effects were blocked. Cocaine decreased the norepinephrine (NE) and serotonin (5-HT) contents of diencephalon-midbrain (DM) and pons-medulla (PM) and increased dopamine (DA) contents in the DM and caudate nucleus (CN) at 20 min after its administration. Haloperidol (0.03 or 0.015 mg/kg) at 30 min postdrug produced opposite effects on the levels of NE, DA and 5-HT in the respective brain areas compared to cocaine. Given in combination, haloperidol reversed the effects of cocaine on the levels of NE, DA and 5-HT. Thus the cocaine-induced behavioral changes and their modification by haloperidol can be correlated to the neurochemical changes produced by these drugs alone or their combination.
Animals↗
Combination of lithium carbonate and haloperidol in schizo-affective disorder: a controlled study.
Lithium carbonate alone has been shown to be inferior to neuroleptics alone in the treatment of excited schizo-affective illness. However, in clinical practice, lithium carbonate and neuroleptics are often combined in this disorder. We report a double-blind five-week controlled trial of lithium carbonate plus haloperidol vs placebo plus haloperidol in the treatment of excited schizo-affective patients. Eighteen patients were studied in each treatment group. Modest but statistically significant differences in favor of lithium carbonate plus haloperidol were found by week 5, using the Brief Psychiatric Rating Scale. Lithium carbonate plus haloperidol was favored both for affective schizo-affectives and for schizophrenic schizo-affectives. Lithium carbonate benefit did not seem to be restricted to affective symptoms only. In the clinical treatment of acute schizo-affective illness, the modest benefits of added lithium carbonate must be weighed against the risks of the drug's toxicity.
Adult↗
Effects of clozapine, thioridazine, perlapine and haloperidol on the metabolism of the biogenic amines in the brain of the rat.
The effects of clozapine, thioridazine, perlapine and haloperidol on the metabolism of the biogenic amines in the brain of the rat have been investigated. Haloperidol, perlapine and thioridazine induce catalepsy and enhance the turnover of DA in the striatum as indicated by the dose-dependent increase in the DA-metabolites, HVA and DOPAC. These effects are due to blockade of dopaminergic transmission, haloperidol being far more potent than perlapine or thiridazine. Clozapine differs from these agents in that it elevates the concentration of striatal DA. The increase of the concentrations of HVA and DOPAC by clozapine is not accompanied by development of catalepsy. Therefore, clozapine seems to influence striatal DA by a mechanism other than DA-receptor blockade. All four drugs enhance the turnover of NA in the brain stem. This effect is probably secondary to the blockade of NA-receptors. There was no correlation between the effects on NA-metabolism and the EEG-arousal inhibitory activities of these agents or their clinical antipsychotic effects. Clozapine increase the concentration of 5-HT and 5-HIAA in the brain. This effect was not seen with the other drugs. Perlapine seems to enhance the turnover of 5-HT, whereas haloperidol reduced the 5-HT concentration. Thioridazine appears to have no effect on the metabolism of 5-HT.
Animals↗
The effect of castration, thyroidectomy and haloperidol upon the turnover rates of dopamine and norepinephrine and the kinetic properties of tyrosine hydroxylase in discrete hypothalamic nuclei of the male rat.
Adult male rats were either castrated, thyroidectomized, or treated with haloperidol and the rates of turnover of dopamine (DA) and norepinephrine (NE) in the median eminence (ME), the arcuate and dorsomedial nuclei of the hypothalamus were estimated from the rate of decay of DA and NE concentrations as determined by radioenzymatic assay following blockade of catecholamine synthesis by alpha-methyl-p-tyrosine. The ME of animals similarly prepared was also examined for changes in the total activity and kinetic properties of tyrosine hydroxylase (TH). Four days following the administration of haloperidol (400 microgram/kg) or 10 days after castration, there was a significant increase in the rate of turnover of DA but not NE in the ME accompanied by an increase in the Vmax but not Km for the substrate or cofactor of TH. Furthermore, the administration of haloperidol to hypophysectomized rats also significantly increased the TH activity in the ME, indicating that such changes may occur independently of any changes in serum prolactin levels. Ten days after thyroidectomy, or three weeks after treatment with prophylthiouracil, there was a significant increase in the turnover rate of DA in both the ME and dorsomedial nucleus but not in the arcuate nucleus. No changes in the turnover rates of NE in any of the three areas were observed following thyroidectomy. In the ME, the increase in turnover of DA was accompanied by an increase in the total TH activity (Vmax) as welll as a decrease in Km for tetrahydrobiopterin but not tyrosine. From these results 4 conclusions were drawn: (1) following halperidol, castration, and thyroidectomy there are increases in the activity of dopaminergic terminals within the ME; (2) castration, haloperidol and thyroidectomy may influence the activity of dopaminergic terminals within the ME by different mechanisms; (3) changes in tyrosine hydroxylase and turnover of catecholamines within the ME may occur independently of changes in prolactin levels; and (4) local recurrent afferent circuits may exist in the arcuate nucleus region of the hypothalamus.
Animals↗