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PubMed1994

Effects of pimozide on cognition in children with Tourette syndrome: interaction with comorbid attention deficit hyperactivity disorder.

Pimozide, a dopamine receptor antagonist, dopamine uptake inhibitor and L-type calcium channel blocker, is used in children suffering from Tourette syndrome (TS), but its effect on frequently comorbid attention deficit hyperactivity disorder (ADHD) is unknown. We have characterized the cognitive effects of pimozide and haloperidol in TS in relation to comorbid ADHD. Sixty-six consecutive outpatients with TS (DSM-III-R), ages 7-16, were randomly assigned to pimozide, haloperidol or medication-free clinical treatment and evaluated cognitively after 6 weeks. Continuous performance task (CPT) and memory search efficiency were compared across treatments. Treatment, comorbid ADHD and their interaction were significant on the CPT task. Pimozide treatment was superior to haloperidol and improved memory search efficiently over the no-drug condition.

Adolescent↗
PubMed1980

Intermittent pimozide versus fluphenazine decanoate as maintenance therapy in chronic schizophrenia.

In a double-blind trial, 34 male chronic schizophrenic day-patients or in-patients in a hostel ward continued on fluphenazine decanoate given mostly once fortnightly or were switched to pimozide, given on four days each week. Over nine months relapse rates were similar for both groups, and while fewer patients on pimozide were prescribed antiparkinsonian drugs one quarter developed buccolingual masticatory dyskinesia. Plasma pimozide levels suggested satisfactory drug compliance. Average plasma prolactin levels were within the normal rage for untreated men in one quarter of non-relapsing patients on pimozide and three quarters on fluphenazine.

Chronic Disease↗
PubMed1985

Synthesis and release of luteinizing hormone in vitro by rat anterior pituitary cells: effects of gallopamil hydrochloride (D600) and pimozide.

We compared the role of Ca2+ in regulating GnRH-induced LH synthesis and release from cultured rat pituitary cells. LH synthesis and release were measured after a 4-h treatment of cells with gallopamil hydrochloride (D600; 1 and 100 microM), a Ca2+ channel blocker, or pimozide (0.5 and 5.0 microM), a calmodulin inhibitor, with or without 1 nM GnRH. LH translation and glycosylation were monitored by measuring incorporation of [14C]alanine and [3H]glucosamine, respectively, into total (cell and medium) immunoprecipitable LH. GnRH significantly (P less than 0.01) increased total [3H]LH (glycosylation), but had no effect on total [14C]LH (translation). D600 significantly (P less than 0.01) depressed (1 microM) and completely blocked (100 microM) GnRH-induced LH glycosylation and release of [3H]LH, [14C]LH, and immunoreactive LH. D600 (100 microM) also reduced (P less than 0.05) total basal synthesis of [14C]LH. Neither dose of D600 altered uptake of [3H]glucosamine, but 100 microM D600 significantly (P less than 0.01) depressed its incorporation into total protein. D600 (100 microM) significantly (P less than 0.01) depressed [14C]alanine uptake and incorporation into total protein. Pimozide significantly (P less than 0.01) reduced, in a dose-related manner, GnRH-induced LH glycosylation, and release of immunoreactive LH, [3H]LH, and [14C]LH. Pimozide did not alter LH translation or uptake of radiolabeled precursors or their incorporation into total protein. These results demonstrate that D600 and pimozide inhibit both GnRH-induced LH glycosylation and release. Thus, the actions of GnRH on LH glycosylation and release are both mediated by similar Ca2+-dependent pathways.

Alanine↗
PubMed1980

Effect of gamma-aminobutyric acid on growth hormone and prolactin secretion in man: influence of pimozide and domperidone.

To investigate the possibility that GH release induced by gamma-aminobutyric acid (GABA) in man is mediated by a dopaminergic mechanism(s), we evaluated the effect of two antidopaminergic compounds, pimozide and domperidone, on the plasma GH response to acute GABA administration (5 g, orally). Only the former compound can freely cross the blood-brain barrier. In 9 normal volunteers, GABA caused a significant increase of plasma GH levels (P < 0.0001 vs. GH levels in a group of 14 controls). In these subjects, pimozide (6 mg/day, orally, for 4 days) significantly blunted the GH elevation induced by GABA (P < 0.01). Unlike pimozide, in 8 additional subjects, domperidone (4 mg injected iv immediately before GABA administration) did not influence the GABA-induced GH response. GABA did not alter either baseline or pimozide-stimulated plasma PRL levels. Likewise, it did not significantly modify the brisk PRL rise after domperidone injection. These findings are consistent with the hypothesis that GABA-stimulated GH secretion is mediated via dopamine release at a suprapituitary level. With regard to PRL secretion, no GABA-dopamine interactions are readily apparent.

Adult↗
PubMed1976

Inhibition of mid-cycle gonadotrophin release in healthy women by pimozide and fusaric acid.

The effects of pimozide, a drug blocking dopamine receptors, and fusaric acid, an inhibitor of dopamine beta-hydroxylase, on mid-cycle release of FSH and LH were studied in 8 healthy women 20-25 years of age. None had used contraceptive drugs for the preceding 10 months. From the menstrual history and serum LH determinations during the normal cycle, mid-cycle gonadotrophin bursts were predicted for the following three cycles. Two days before and after the expected gonadotrophin surge were regarded as sufficient for the drug tests. Pimozide (initially 2 mg, then 1 mg/day) and fusaric acid (600 mg/day) were administered in a randomized cross-over study. The mid-cycle LH values were reduced from the control level of 56 +/- 10 mIU/ml (mean +/- SE) to 22 +/- 4 mIU/ml by pimozide (P less than 0.001) and to 17 +/- 5 mIU/ml by fusaric acid (P less than 0.001). The serum FSH level was 9 +/- 2 mIU/ml on the day of the LH surge and did not change significantly during treatment with either drug. The LH and FSH responses to synthetic LRF (100 mug iv) were not changed by pimozide or fusaric acid. The rise of basal temperature associated with ovulation was not affected by the drugs. These results suggest that suprapituitary noradrenergic and dopaminergic neurotransmitters are involved in the regulation of mid-cycle gonadotrophin secretion in women.

Adult↗
PubMed1996

The successful treatment of a gender dysphoric patient with pimozide.

OBJECTIVE: The case is reported of a gender dysphoric patient who responded successfully to pharmacotherapy with pimozide. CLINICAL PICTURE: An adult male patient with a borderline learning disability presented with cross-dressing and a strong wish to undergo a sex change. TREATMENT: Supportive psychotherapy and pharmacotherapy with pimozide was tried. OUTCOME: There was an excellent response to pimozide 2 mg daily, with a cessation of both cross-dressing and the wish for sex reassignment. When, after 1 year, the dose was reduced to 1 mg daily, there was a rapid return of the cross-dressing and the wish for sex reassignment. An increase in the dose again led to a remission which has been maintained since then. CONCLUSION: Pharmacotherapy with pimozide should be considered in cases of doubtful gender dysphoria.

Adult↗
PubMed1997

Pimozide-induced depression in men who stutter.

BACKGROUND: Neuroleptic-related dysphoric reactions are well recognized in the context of psychiatric disorders, especially in association with extrapyramidal side effects. Very few controlled data exist regarding the effects of neuroleptics on the mood of psychiatrically "normal" subjects. In this study, the depressogenic effect of the neuroleptic drug pimozide was assessed in men without psychiatric disorders. METHOD: Eight men with developmental stuttering but no past or present psychiatric illness participated in a double-blind, placebo-controlled study assessing the effect of 6 weeks of pimozide treatment on speech fluency and mood. RESULTS: Four of the seven subjects who were compliant with the treatment developed marked depressive symptoms. No clear association was found between these reactions and pimozide dose, blood level, or degree of neurologic side effects. Symptoms abated soon after drug discontinuation. CONCLUSION: Pimozide induced significant depressive symptoms in this group of psychiatrically normal men who stutter. Neuroleptic drugs may have a causal effect in the induction of depression in psychiatrically normal subjects, ostensibly independent of dose or severity of neurologic side effects.

Adolescent↗
PubMed2001

Risperidone versus pimozide in Tourette's disorder: a comparative double-blind parallel-group study.

BACKGROUND: The treatment of Tourette's disorder with classical neuroleptics is limited by their side effects. Risperidone is a new efficacious antipsychotic with a low propensity for extrapyramidal side effects. To establish risperidone's therapeutic potential in Tourette's disorder, we studied the safety and efficacy of risperidone in comparison with pimozide in patients with Tourette's disorder diagnosed according to DSM-III-R. METHOD: In a 12-week, multicenter, double-blind, parallel-group study, 26 patients were treated with risperidone (mean daily dose = 3.8 mg), and 24 patients were treated with pimozide (mean daily dose = 2.9 mg). RESULTS: There was significant improvement of tics with respect to the Tourette's Symptom Severity Scale (TSSS) for both groups. Forty-one patients completed the study. At endpoint, 54% (14/26) of the risperidone patients and 38% (9/24) of the pimozide patients had only very mild or no symptoms on the global severity rating of the TSSS. Both treatment groups had improved significantly at endpoint in regard to Global Assessment of Functioning and Clinical Global Impressions scale outcomes. Symptoms of anxiety and depressive mood improved significantly from baseline in both groups. Obsessive-compulsive behavior improvement reached significance only in the risperidone group. Although the severity of extrapyramidal side effects was low in both groups, fewer patients in the risperidone group reported extrapyramidal side effects (N = 4) compared with the pimozide group (N = 8). Depression, fatigue, and somnolence were reported as the most prominent side effects in both treatment groups. CONCLUSION: Both drugs were efficacious and well tolerated in patients with Tourette's disorder. Risperidone may become the first-line drug in the treatment of Tourette's disorder owing to a more favorable efficacy and tolerability profile.

Adolescent↗
PubMed1992

Tamoxifen-resistant human breast cancer cell growth: inhibition by thioridazine, pimozide and the calmodulin antagonist, W-13.

Estrogen receptor (ER)-negative human breast cancer cell lines (MDA-MB-231 and MDA-MB-435) and ER-positive derivatives of the MCF-7 cell line selected for growth in the presence of antiestrogens (LY2 and RR) were used as in vitro models of tamoxifen-resistant human breast cancer in this study. The sensitivity of the tamoxifen-sensitive (MCF-7) and tamoxifen-resistant human breast cancer cell growth to two noncytotoxic neuroleptic drugs, pimozide and thioridazine, and the anticalmodulin agent, W-13, were compared. Inhibition of cell growth was measured as a decrease in cell number following a 72-h incubation with drug. Growth of the ER-negative cell lines MDA-MB-231 and MDA-MB-435 was inhibited by all three drugs. The average Ki values in these two lines were 6.3 and 3.8 microM for pimozide and 4.1 and 15 microM for thioridazine, respectively. Both ER-negative cell lines were more sensitive than MCF-7 cells to growth inhibition by W-13. MCF-7 cells selected for antiestrogen resistance were sensitive to growth inhibition by W-13 and thioridazine (LY2, average Ki = 10.4 microM; RR, average Ki = 5.2 microM). LY2 and RR cells were resistant to pimozide except when treated with estradiol (Ki = 4.6 and 7.9 microM, respectively). Pimozide, thioridazine and W-13 all exerted different effects on the distribution of human breast cancer cells within the cell cycle, suggesting that each drug may utilize a distinct pathway for inhibition of cell growth. We conclude that all three drugs are potential noncytotoxic alternatives to tamoxifen for the treatment of tamoxifen-resistant human breast cancer.

Breast Neoplasms↗
PubMed2006

Fetal exposure to pimozide: a case report.

BACKGROUND: Pimozide is an antidopaminergic, antipsychotic drug. Exposure during human pregnancy has not been reported previously, and recommendations on its use are based on extrapolation from other antipsychotics with antidopaminergic activity. CASE: A 26-year-old woman had Gilles de la Tourette syndrome and obsessive-compulsive disorder. It was not possible to discontinue pimozide during pregnancy, although the dosage was reduced to 1 mg daily. In addition, she was treated with 20 mg fluoxetine until gestational week 27. By request of the patient, elective cesarean section was scheduled for week 38. As a precaution, pimozide was withdrawn 2 weeks prior to the section. During this period the patient's symptoms severely intensified, and an emergency cesarean section had to be performed at 36 weeks. A healthy male infant weighing 2,448 g was delivered. Pediatric examination of the infant and electroencephalogram demonstrated no neurologic abnormalities. On day 4 both mother and infant were discharged. CONCLUSION: This is the first published report on fetal exposure to pimozide.

Adult↗
PubMed1991

[Three cases of hyponatremia during administration of pimozide].

Three patients with hyponatremia were found at an residential home of mental developmental delay. Because pimozide had been administered to all of them, it was suggested that pimozide might have induced compulsive water drinking resulting in hyponatremia. To my knowledge, there has been no previous report that pimozide may induce hyponatremia. As children with mental developmental delay and/or autism frequently develop epilepsy, hyponatremia should be included in the differential diagnosis of convulsive seizures. Particularly when antipsychotic drugs such as pimozide have been given, we should pay attention to polydipsia, polyuria and/or general malaise and prevent hyponatremia.

Adolescent↗
PubMed1990

Regulation of prolactin gene transcription in vivo: interactions between estrogen, pimozide, and alpha-ergocryptine.

A single injection of pimozide, a dopamine antagonist, rapidly stimulated prolactin (PRL) gene transcription in male rats, whereas an injection of alpha-ergocryptine, a dopamine agonist, rapidly inhibited PRL gene transcription. Pretreatment with cycloheximide blocked the induction of PRL gene transcription by pimozide but had no effect on the inhibition of transcription by ergocryptine. The interactions between ergocryptine and 16 alpha-estradiol, an estrogen that stimulates PRL gene transcription through two independent mechanisms, were also examined. Pretreatment with ergocryptine had no effect on the ability of 16 alpha-estradiol to stimulate PRL gene transcription through a mechanism that is most probably mediated directly by the anterior pituitary estrogen receptor. However, ergocryptine pretreatment did block the ability of 16 alpha-estradiol to stimulate transcription through a second, indirect, mechanism. This ergot alkaloid also blocked the ability of pimozide to stimulate PRL gene transcription. Pretreatment with 16 alpha-estradiol had no effect on the ability of ergocryptine to inhibit PRL gene transcription, indicating that this estrogen did not grossly alter the responsiveness of the anterior pituitary to the dopamine agonist. The similarities between the effects of 16 alpha-estradiol, via the indirect mechanism, and pimozide on PRL gene transcription suggest that estrogen may stimulate PRL gene transcription in vivo in part by reducing the release of dopamine from hypothalamic neurons.

Animals↗
PubMed1991

Genetics, haloperidol and pimozide: a comparative study in two mouse strains.

Haloperidol and pimozide are the only medications approved in management of Tourette's syndrome, thought due to dopaminergic overactivity with a possible genetic trait. The effect of equal dose regimens of these drugs on some brain biogenic amines and major acidic metabolites was studied in two genetically different strains of mice. These drugs exerted strain-dependent effect on regional brain levels of the compounds measured. The results suggest a higher turnover of striatal dopamine by haloperidol than by pimozide in the albino BALB/c but not in the black C57BL/6 mouse strain which may explain the high incidences of haloperidol-induced extrapyramidal side effects. Conversely, a greater decrease in serotonin turnover by pimozide than by haloperidol was apparent in two brain regions of C57BL/6 but not in BALB/c mice which may contribute to the unwanted sedative effect reported for pimozide. The results suggest the possible contribution of genetic factors to cerebral potency of these neuroleptics which may explain variable therapeutic response and sensitivity to drug-produced toxicity in Tourette's syndrome.

Animals↗
PubMed1977

Pimozide versus fluphenazine in ambulatory schizophrenics: A 12-month comparison study.

In this study, chronic schizophrenic outpatients who had been maintained on various neuroleptics for an average of about 4 years had their previous medications (approximately equivalent to 695 mg of chlorpromazine per day) changed abruptly to either pimozide or fluphenazine given in single daily oral doses on a double-blind basis for a period of 52 weeks. Average daily doses were pimozide 9.6 mg and fluphenazine 12.5 mg. Measurements of the therapeutic effects of the two drugs were made immediately prior to starting the study, at the end of the 2nd and 4th weeks, and thereafter every 4th week to the end of the study. Three psychometric scales were used for evaluation: Brief Psychiatric Rating Scale (BPRS); Evaluation of Social Functioning (ESFR); and Clinical Global Impressions (CGI). In addition, patients participated in a Social Adjustment Inventory (SAI) evaluation. Statistical analysis with the use of several statistical techniques for between- and within-drug group comparisons revealed that pimozide and fluphenazine were equally effective in maintaining control of symptomatology of chronic schizophrenics at a level commensurate with or better than that provided by their previous medication. Side effects were characteristic of marketed neuroleptics, similar in severity and occurrence between study-drug groups, mainly extrapyramidal symptoms, and readily controlled with antiparkinsonian medication. Pimozide, slightly more potent than fluphenazine, proved to be equally effective for the long-term management of chronic schizophrenic patients.

Adult↗
PubMed1986

Pimozide treatment for delusion of infestation.

Pimozide was tried in the treatment of delusion of parasitosis (a type of monosymptomatic hypochondriacal psychosis), a syndrome that is found with increasing frequency. Ten patients were selected on the basis of unambiguously defined psychopathological criteria. Pimozide therapy was assessed by means of placebo control and the double-blind method using a rating scale evolved for this particular therapy. The results have quite definitely proved the effect of small doses (two to eight mg per day) of pimozide compared to the administration of a placebo. The very few side-effects observed could easily be influenced. The dynamics of the regression of the psychopathological symptoms suggest that the efficacy of pimozide therapy is decisively linked to the central dopamine receptor blocking effect of the drug.

Aged↗
PubMed1983

Effects of pimozide and apomorphine on insulin secretion from the perfused rat pancreas.

The effects of apomorphine, a partial agonist of dopamine, and of pimozide, an agent commonly used as an antagonist of dopamine, on insulin secretion from the perfused rat pancreas were studied. Apomorphine (10 and 100 microM) significantly reduced the insulin released in response to a stimulating glucose load. As judged from the perfusion pressure vasoconstriction could not account for the inhibitory action. The effect of apomorphine was not reversed by phentolamine infused to block alpha-receptors. Pimozide (1 microM) slightly weakened the inhibitory effect of apomorphine (10 microM) but failed to completely restore a normal secretion. An increase of the pimozide concentration (10 microM) revealed, however, that the agent itself reduced the glucose-induced insulin release. Thus a differentiation of dopamine agonistic and antagonistic effects could not be achieved with the aid of pimozide.

Animals↗
PubMed1993

Differential tolerance to the behavioral effects of chronic pimozide and clozapine on multiple random interval responding in rats.

The behavioral effects of 10 days of chronic administration of the typical neuroleptic, pimozide, and the atypical neuroleptic, clozapine, were compared on a schedule of multiple random interval responding for food reinforcement and on photocell activity in rats. The low doses of both neuroleptics (0.125mg/kg pimozide, 1.25mg/kg clozapine) had little effect on any of the dependent variables measured. The high doses (1.0mg/kg pimozide, 10.0mg/kg clozapine) significantly disrupted response rates and reinforcement rates and significantly increased response duration when the drugs were first administered. Chronic administration, however, resulted in different profiles for the two drugs. While tolerance developed to the disruptive effects of clozapine, tolerance did not develop to the disruptive effects of pimozide and, on some dependent measures, an increased sensitivity developed. No tolerance developed to the disruptive effects of either drug on photocell activity. The effects of the drugs depended on the reinforcement density of the operant schedule.

Journal Article↗
PubMed2001

The antipsychotic drugs sertindole and pimozide block erg3, a human brain K(+) channel.

The antipsychotic drugs sertindole and pimozide are known to prolong the QT interval on the electrocardiogram via a high affinity block of the cardiac K(+) channel known as HERG (human ether-a-go-go-related gene; erg1). We wished to test whether these drugs also displayed high affinity for the related neuronal K(+) channel erg3. The cDNA encoding erg3 channel was cloned from a human brain library. Northern analysis confirmed that the channel was localized to brain relative to other tissues including heart, liver and lung. Within the brain, erg3 was expressed in higher amounts in the frontal lobe and cerebellum relative to the temporal, parietal and occipital lobes. Transient expression of erg3 in Chinese hamster ovary cells produced outwardly directed K(+) currents that activated at approximately -50 mV and produced a large transient component at positive membrane potentials. Inward tail currents measured at -100 mV were blocked in a dose-dependent fashion by sertindole resulting in an IC(50) value of 43 nM. Significant inhibition was observed at concentrations as low as 3 nM. Block of erg3 by sertindole also displayed a positive voltage-dependence. Pimozide blocked erg3 channel currents with an IC(50) of 103 nM and significant inhibition was noted at concentrations of 10 nM and higher. We conclude that erg3 can be blocked by certain antipsychotic drugs like sertindole and pimozide. Inhibition of erg3 or related K(+) channels in the brain may contribute to the efficacy/side effect profiles of some antipsychotic drugs.

Animals↗