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In a clinical and psychopathological study of alcohol-dependent patients presenting with emotional disturbances and hypomaniac syndrome, expediency was shown of use of a neuroleptic drug preparation pimozide in the treatment of hypomaniac syndrome of alcohol genesis.
In a double blind placebo controlled clinical evaluation of maintenance therapy in chronic schizophrenic female outpatients, thiordazine in single daily doses not exceeding 375 mg./day for 6 months was shown to be effective maintenance treatment compared with PL, thereby establishing the sensitivity of the experiment. Pimozide was also shown to be effective in a single oral dose not exceeding 16 mg./day and comparable overall to the standard drug. The experimental design was based on the anticipated retrogression of PL treated subjects during the 6-month study period, which was reflected in 5 of 9 (56%) "treatment failures" in the PL group compared to 2 of 14 (14%) and 2 of 12 (17%) in the THI and PIM groups, respectively. In addition, in some instances improvement over baseline evaluations was noted in both drug groups, particularly on global impression. Though some items of the BPRS exhibited Drug: PL differences, the scale in general was felt to be rather insensitive for this kind of study. Social adjustment ratings on a special scale completed by the patients and families alike, were also found to be insensitive to treatment differences. Side effects most often seen with THI were sedation, EKG and liver function abnormalities. Headache and restlessness occurred most often with PIM. Extrapyramidal symptoms and insomnia were seen most often with PIM and PL equally.
Current medication for Huntingtons chorea is based on compounds which affect the activity of acetylcholine and dopamine in the basal ganglia and is unsatisfactory. This report describes a small clinical trial of dopamine antagonists, tetrabenazine (Nitoman) and pimozide (Orap). Improvement was early and striking but was not maintained over the trial period of 83 weeks.
The present study reports the comparative effects of pimozide (PMZ; 0.1, 0.3 and 1.0 mg/kg) and clozapine (CZP; 1.0, 3.0 and 10.0 mg/kg) on fixed-interval 60-sec responding after acute and chronic administration and on the acquisition of schedule-induced drinking (SID) during a chronic dosing procedure. Both the 0.3 and the 1.0 mg/kg of PMZ groups responded significantly less than vehicle controls after acute dosing without disrupting the operant response patterns as measured by index of curvature (IOC), and these effects persisted for 38 days of treatment. Acute treatment with 3.0 and 10.0 mg/kg of CZP significantly suppressed operant response rates and disrupted the pattern of operant responding, in that the IOC was significantly lower for these subjects than for vehicle controls. The CZP-treated animals gradually developed tolerance to the drug effects and were performing at vehicle control levels after Day 7 of treatment. SID was assessed from Day 19 through Day 38 of neuroleptic treatment. PMZ suppressed the acquisition of SID. Animals treated with 1.0 and 0.3 mg/kg of PMZ consumed less water than controls and did not develop the postpellet drinking pattern characteristic of SID. Both the vehicle and 0.1 mg/kg of PMZ groups increased the amount of water they consumed across the 10 blocks of sessions. A dose-related suppression of SID also was noted for CZP-treated rats. Vehicle controls and three of the subjects treated with 10.0 mg/kg of CZP acquired the SID behavior. These animals gradually increased the amount of water they consumed across sessions and drank in a temporal pattern consistent with SID.(ABSTRACT TRUNCATED AT 250 WORDS)
Using [14C]-2-deoxyglucose autoradiography, we determined which forebrain and diencephalic areas showed metabolic alterations in response to unilateral electrical stimulation of the posterior medial forebrain bundle at parameters chosen to produce a just-submaximal rewarding effect. At these parameters, only a few areas were activated. There was no detectable activation anterior or dorsal to the genu of the corpus callosum. Just anterior to the anterior commissure, there was strong activation of the vertical limb of the diagonal band of Broca, with a focus in the nucleus of the diagonal band. Just posterior to the anterior commissure, there was strong activation of compartment "c" of the medial forebrain bundle (MFB), with weaker activation of the bed nucleus of the stria terminalis and the medial preoptic area. At midhypothalamic levels, the dorsolateral, dorsomedial, and ventral MFB all showed activation. There was bilateral suppression of activity in the lateral habenula. Activation appeared to end in the anterior ventral tegmental area of Tsai. Reward-blocking doses of the neuroleptic pimozide activated the caudate and the lateral habenula but did not alter any of the unilateral effects of stimulation. Using longer pulse durations and/or shifting the site of stimulation to the substantia nigra activated many of the systems not activated in the first experiment, including all of the major dopaminergic projection systems, proving the capacity of the technique to reveal activation of these systems. The results permit one to define a discrete projection system that merits electrophysiological investigation as a likely substrate for the rewarding effect of MFB stimulation. They also suggest that dopaminergic projection systems may not form part of the reward pathway itself.
Twelve male Long Evans rats, trained to lever press using 10% (v/v) oral ethanol reinforcement, were maintained with ad lib access to food and water in the home cage. After stabilization of responding, the rats were randomly divided into two groups: Group P received pimozide (PIM) injections (0.1 to 0.5 mg/kg) and Group A received d-amphetamine (DEX) injections (0.05 to 0.5 mg/kg). Following the sequence of either PIM or Dex injections, all rats were given four different combinations of PIM + DEX injections. The lower doses of amphetamine did not affect responding, but 0.5 mg/kg significantly reduced responding. All PIM doses except the lowest reduced responding. The combined PIM + DEX doses all reduced responding, in some cases further than either constituent dose alone. Next, all rats were reduced to 80% of their free feeding weights by food restriction, and tested with 0.25 mg/kg DEX, 0.1 mg/kg PIM, and 0.1 PIM + 0.25 DEX. As a result of food restriction, baseline responding increased significantly. The 0.25 mg/kg DEX dose tended to increase responding even above this baseline increase, while both PIM and PIM + DEX reduced responding.
I.V. administration of 300 mg. Pyridoxine caused an acute fall in prolactin (PRL) plasma levels in six normal subjects. Like levodopa, pyridoxine suppressed the increase in PRL secretion induced by treatment with pimozide, a specific dopamine receptor blocking agent. These findings further support the hypothesis that vitamin B6 stimulates dopaminergic activity at hypothalamic and/or hypophyseal level.
Chlorpromazine (CPZ) a neuroleptic which has both antiadrenergic and antidopaminergic activity when administered in doses of 5 to 25 mg/kg s.c. inhibited ovulation and induced pseudopregnancy. Pimozide which possesses only an antidopaminergic action induced only pseudopregnancy (in doses between 0.05-10 mg/kg s.c.). Apomorphine (APO), a dopaminergic agonist, prevented the pseudopregnant effect of both neuroleptics, especially of CPZ, but failed to counteract the ovulation-blocking action of CPZ. APO itself had an antiovulatory action, but only in large doses (above 5 mg/kg s.c.), and only in a few animals. Our data plead for the importance of dopaminergic mechanisms in the inhibition of prolactin secretion (by means of PIF) and for the stimulatory role of adrenergic transmission in the ovulation process (by means of LRF). These results fail to support the proposed stimulatory role of dopamine on the LRF secretion. On the contrary, they do not exclude the possibility of its inhibitory action.
Two identical groups of schizophrenic patients were treated for 28 days randomized with 3 and 8 mg of pimozide. In the antipsychotic efficacy no difference could be seen. Difference was in side effects: The 8-mg group had three times more extrapyramidal signs, mostly akathisia and agitation, and needed seven times more minor tranquilizer than the 3-mg group. Severe agitation as a psychotic symptom was equal in both groups. Preference therefore is given to the smaller dosage.
An open, 12-week study of pimozide (8 mg per day) used concurrently with previous maintenance therapy was carried out to investigate improvements in the social behaviour of 20 chronic schizophrenics. Ward behaviour, work habits and mental status all showed statistically significant improvement after 8 weeks of treatment. The incidence of side-effects was low.
A case of onychotillomania in a 70-year-old woman is presented. The disease had persisted for 51/2 years. All her fingernails were plucked away. The patient had a fixed hypochondrial delusion of nail disease. After treatment with pimozide (Orap) for 7 months the nails were normal.
In experiments conducted on adult female Wistar rats, lisuride hydrogen maleate, injected before the critical period of proestrus (between 11 h-13 h) in a single s.c. dose of 0.125 mg/kg body, significantly elevated the preovulatory gonadotropin surge and slightly, non-significantly lowered that of prolactin (assessed between 15-16 h). Pimozide, a selective antidopaminergic neuroleptic, injected according to the same schedule in a dose of 2.5 mg/kg body, strongly augmented the LH surge and also prolactin secretion. Thus, stimulation of gonadotropin secretion by lisuride cannot be ascribed to its dopaminergic agonistic action, but may be attributed to its antiserotoninic activity or to the action on the presynaptic dopamine receptors of the tuberoinfundibular neurons, reducing their inhibitory influence on the gonadotropin surge. The results plead for the inhibitory role of DA in the LH and prolactin secretion; 5-HT may have a similar action in the preovulatory gonadotropin surge and a stimulatory one in the surge of prolactin.
A recent article in the Archives described the severe problems encountered in trying to treat patients with delusions of parasitosis. The present article describes four such cases, which fall into the larger category of monosymptomatic hypochondriacal psychoses, conditions that appear to be related to the paranoid disorders. Evidence is accumulating that such cases may respond very specifically to treatment with pimozide, a relatively new psychotropic medication. This drug keeps the symptoms in remission but does not effect a cure; nevertheless, it may represent a highly important advance in therapy in a condition traditionally regarded as virtually untreatable.
Inhalation of ethanol vapor (28 mg/l) for 24 hr caused a reduction of body temperature in rats. The mean peak blood ethanol concentration was 3.36 +/- 0.14 mg/ml. When ethanol (2 g/kg i.p.) was administered 48 hr after termination of ethanol inhalation, the ethanol vapor-treated animals maintained normal body temperatures despite the presence of blood ethanol concentrations (1.81 +/- 0.04 mg/ml) which caused hypothermia in control animals. The rate of clearance of ethanol from blood was found to be 0.34 +/- 0.01 mg/ml/hr in ethanol vapor-treated and control animals when ethanol was administered acutely 48 hr after the inhalation period. Animals tolerant to the hypothermic effect of ethanol demonstrated diminished sensitivity to the hypothermic effect of clonidine (50 micrograms/kg s.c.). Pretreatment of naive animals with the dopaminergic blocker, pimozide, significantly attenuated the hypothermic response to acute ethanol administration (2 g/kg i.p.) and potentiated the hypothermic response to acute clonidine administration. A dopaminergic mechanism may partially mediate the reduction in body temperature associated with acute ethanol administration.
In the present study, the value of pimozide, rapidly instituted at an optimal maintenance dose, for facilitating the social re-integration was assessed in 24 psychotic, mainly newly admitted, patients. The study comprised three stages spread over about 2 months, in which an optimal daily dose was individually fixed during stage 2 and maintained during stage 3. At the selection and at the end of stage 1, 2 and 3 (or at discharge) the psychiatric status of the patients was evaluated by means of the "Brief Psychiatric Rating Scale" and the resocialization readiness by means of the "Discharge Readiness Questionnaire". At completion of the trial 16 patients were ready for discharge.
Classical conditioning of the nictitating membrane response of the rabbit was accomplished by presenting tone and light conditioned stimuli for 800 msec before delivery of the unconditioned stimulus, consisting of a 100-msec electric shock to the skin over the paraorbital region of the head. Both haloperidol (250 microgram/kg i.v.) and an equimolar dose of pimozide (308 microgram/kg i.v.) significantly retarded the rate of acquisition of conditioned responses (CRs). Control experiments conducted with separate groups of rabbits indicated that the retardant effect of haloperidol on CR acquisition was not due to an effect on sensitization, pseudoconditioning, base-line responding or the unconditioned nictitating membrane reflex. In previously trained animals, haloperidol produced a significant (12.0 ob) elevation in the intensity threshold of a tone conditioned stimulus for elicitation of CRs. In a separate group of animals, and before any conditioning, haloperidol significantly blocked the amplitude and duration of a tone-induced facilitation of the nictitating membrane reflex. It was concluded that haloperidol blocks both the conditioned and unconditioned excitatory properties of a tone and this accounts for its ability to retard the rate of CR acquisition.
Chromatin structure and nucleohistone pattern were investigated histochemically in the neutrophils of 11 schizophrenics and 16 healthy controls. Compared to controls, all schizophrenic parents prior to medication showed a distinctly different histochemical pattern consisting of increased concentration and abnormal distribution of nucleohistones. This pattern has been attributed to an increase of arginine-rich histones in schizophrenics. Pimozide administration exerted a normalizing effect on the nucleohistone distribution pattern. These findings further support our view that genomic expression abnormalities may be related to schizophrenic illness.
20 non-psychotic aged (more than 60 years old) in-patients with behavior troubles were treated with pimozide in an open study for more than 12 weeks. Such symptoms deriving from the emotional sphere, mainly the aggressivity, had the best improvement rate. Together with this could also be seen an improvement of the social behavior. The dosage optimum was between 3 and 4 mg p.d., the improvement period seems to reach from the second to the eighth week. Extrapyramidal side-effects were rare, two patients developed, after more than nine months of therapy and long after the study had finished, a tardive hyperkinesia which was reversible after the withdrawal of the substance.