Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions.

BACKGROUND: Psychiatric medications are widely prescribed in the USA. Many antipsychotics cause serum hyperprolactinemia as an adverse side effect; prolactin-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling both induces cell differentiation and suppresses apoptosis. It is controversial whether these antipsychotics increase breast cancer risk. METHODS: We investigated the impact of several antipsychotics on mammary tumorigenesis initiated by retrovirus-mediated delivery of either ErbB2 or HRas or by transgenic expression of Wnt-1. RESULTS: We found that the two hyperprolactinemia-inducing antipsychotics, risperidone and pimozide, prompted precancerous lesions to progress to cancer while aripiprazole, which did not cause hyperprolactinemia, did not. We observed that risperidone and pimozide (but not aripiprazole) caused precancerous cells to activate STAT5 and suppress apoptosis while exerting no impact on proliferation. Importantly, we demonstrated that these effects of antipsychotics on early lesions required the STAT5 gene function. Furthermore, we showed that only two-week treatment of mice with ruxolitinib, a JAK1/2 inhibitor, blocked STAT5 activation, restored apoptosis, and prevented early lesion progression. CONCLUSIONS: Hyperprolactinemia-inducing antipsychotics instigate precancerous cells to progress to cancer via JAK/STAT5 to suppress the apoptosis anticancer barrier, and these cancer-promoting effects can be prevented by prophylactic anti-JAK/STAT5 treatment. This preclinical work exposes a potential breast cancer risk from hyperprolactinemia-inducing antipsychotics in certain patients and suggests a chemoprevention regime that is relatively easy to implement compared to the standard 5-year anti-estrogenic treatment in women who have or likely have already developed precancerous lesions while also requiring hyperprolactinemia-inducing antipsychotics.

GABA-A Alpha 2/3 but Not Alpha 1 Receptor Subunit Ligand Inhibits Harmaline and Pimozide-Induced Tremor in Rats.

Treatment of tremors, such as in essential tremor (ET) and Parkinson's disease (PD) is mostly ineffective. Exact tremor pathomechanisms are unknown and relevant animal models are missing. GABA-A receptor is a target for tremorolytic medications, but current non-selective drugs produce side effects and have safety liabilities. The aim of this study was a search for GABA-A subunit-specific tremorolytics using different tremor-generating mechanisms. Two selective positive allosteric modulators (PAMs) were tested. Zolpidem, targeting GABA-A α1, was not effective in models of harmaline-induced ET, pimozide- or tetrabenazine-induced tremulous jaw movements (TJMs), while the novel GABA-A α2/3 selective MP-III-024 significantly reduced both the harmaline-induced ET tremor and pimozide-induced TJMs. While zolpidem decreased the locomotor activity of the rats, MP-III-024 produced small increases. These results provide important new clues into tremor suppression mechanisms initiated by the enhancement of GABA-driven inhibition in pathways controlled by α2/3 but not α1 containing GABA-A receptors. Tremor suppression by MP-III-024 provides a compelling reason to consider selective PAMs targeting α2/3-containing GABA-A receptors as novel therapeutic drug targets for ET and PD-associated tremor. The possibility of the improved tolerability and safety of this mechanism over non-selective GABA potentiation provides an additional rationale to further pursue the selective α2/3 hypothesis.

Blockade of adenosine A2A receptors inhibits Tremulous Jaw Movements as well as expression of zif-268 and GAD65 mRNAs in brain motor structures.

Tremor is one of the motor symptoms of Parkinson's disease (PD), present also in neuroleptic-induced parkinsonism. Tremulous Jaw Movements (TJMs) are suggested to be a well-validated rodent model of PD resting tremor. TJMs can be induced by typical antipsychotics and are known to be reduced by different drugs, including adenosine A2A receptor antagonists. The aim of the present study was to search for brain structures involved in the tremorolytic action of SCH58261, a selective A2A receptor antagonist, in TJMs induced by subchronic pimozide. Besides TJMs, we evaluated in the same animals the expression of zif-268 mRNA (neuronal responsiveness marker), and mRNA levels for glutamic acid decarboxylase 65-kDa isoform (GAD65) and vesicular glutamate transporters 1 and 2 (vGluT1/2) in selected brain structures, as markers of GABAergic and glutamatergic neurons, respectively. We found that SCH58261 reduced the pimozide-induced TJMs. Pimozide increased the zif-268 mRNA level in the striatum, nucleus accumbens (NAc) core, and substantia nigra pars reticulata (SNr). Additionally, it increased GAD65 mRNA in the striatum and SNr, and vGluT2 mRNA levels in the subthalamic nucleus (STN). A positive correlation between zif-268, GAD65 and vGluT2 mRNAs and TJMs was found. SCH58261 reversed the pimozide-increased zif-268 mRNA in the striatum and NAc core and GAD65 mRNA in the striatum and SNr. In contrast, SCH58261 did not influence vGluT2 mRNA in STN. The present study suggests an importance of the striato-subthalamo-nigro-thalamic circuit in neuroleptic-induced TJMs. The tremorolytic effect of A2A receptor blockade seems to involve this circuit bypassing, however, STN.

Aripiprazole as a viable alternative for treating delusions of parasitosis.

Delusions of parasitosis (DOP) is a psychiatric disorder characterized by the fixed false belief that one is infested with parasites or other organisms. Historically, pimozide, a first-generation antipsychotic, has been the treatment of choice for DOP, although there is risk for serious adverse effects including extrapyramidal symptoms, QTc prolongation and tardive dyskinesia. Recently, there have been several reports describing the effectiveness of second-generation antipsychotics (SGAs), but these agents have their own unique adverse effects, specifically metabolic changes with olanzapine, sedation with quetiapine and hyperprolactinemia with risperidone. Aripiprazole is a novel, third-generation antipsychotic with comparable efficacy to SGAs, but a more favorable side effect profile. Successful treatment of DOP with aripiprazole has recently been described in the psychiatric and dermatologic literature. The authors present another report to support the use of aripiprazole as an efficacious and safe alternative for treating DOP.

STF-62247 and pimozide induce autophagy and autophagic cell death in mouse embryonic fibroblasts.

Induction of autophagy can have beneficial effects in several human diseases, e.g. cancer and neurodegenerative diseases (ND). Here, we therefore evaluated the potential of two novel autophagy-inducing compounds, i.e. STF-62247 and pimozide, to stimulate autophagy as well as autophagic cell death (ACD) using mouse embryonic fibroblasts (MEFs) as a cellular model. Importantly, both STF-62247 and pimozide triggered several hallmarks of autophagy in MEFs, i.e. enhanced levels of LC3B-II protein, its accumulation at distinct cytosolic sites and increase of the autophagic flux. Intriguingly, autophagy induction by STF-62247 and pimozide resulted in cell death that was significantly reduced in ATG5- or ATG7-deficient MEFs. Consistent with ACD induction, pharmacological inhibitors of apoptosis, necroptosis or ferroptosis failed to protect MEFs from STF-62247- or pimozide-triggered cell death. Interestingly, at subtoxic concentrations, pimozide stimulated fragmentation of the mitochondrial network, degradation of mitochondrial proteins (i.e. mitofusin-2 and cytochrome c oxidase IV (COXIV)) as well as a decrease of the mitochondrial mass, indicative of autophagic degradation of mitochondria by pimozide. In conclusion, this study provides novel insights into the induction of selective autophagy as well as ACD by STF-62247 and pimozide in MEFs.

Pimozide for tics in Tourette's syndrome.

BACKGROUND: Neuroleptic drugs with potent D-2 receptor blocking properties have been the traditional treatment for tics caused by Tourette Syndrome. Pimozide is the most studied of these. Use of these medications is declining because of concerns about side effects, and new atypical neuroleptics are now available. The true benefit and risks associated with pimozide compared to other drugs is not known. OBJECTIVES: To evaluate the efficacy and harms of pimozide in comparison to placebo or other medications in the treatment of tics in Tourette Syndrome. SEARCH STRATEGY: We cross-referenced pimozide and its proprietary names with Tourette Syndrome and its derivations, as MeSH headings and as text words, and searched the Cochrane Movement Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 4), MEDLINE (1950-April 2007), and EMBASE (1980-April 2007). Reference lists of relevant articles were reviewed for additional trials. SELECTION CRITERIA: All randomized, controlled, double blind studies comparing pimozide to placebo or other medications for the treatment of tics in Tourette Syndrome were considered for inclusion in this review. Both parallel group and crossover studies of children or adults, at any dose and for any duration, were included. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by two authors onto standardized forms and disagreements were resolved by discussion. MAIN RESULTS: Six randomized controlled trials were included (total 162 participants, age range 7 to 53 years). Pimozide was compared with: placebo and haloperidol (two trials), placebo (one trial), haloperidol (one trial), and risperidone (two trials). Methodological quality was rated 'fair' for all studies. Studies used different outcome measurement scales for assessing tic severity and adverse effects. Significant clinical heterogeneity made meta-analysis inappropriate. Pimozide was superior to placebo in three studies, though it caused more side effects than placebo in one of these. Pimozide was inferior to haloperidol in one of three studies (the other two showed no significant difference between the drugs), which also showed significantly fewer side effects associated with pimozide. No significant differences between pimozide and risperidone were detected. AUTHORS' CONCLUSIONS: Pimozide is an effective treatment for tics in Tourette Syndrome, though the number of trials comparing its effect to placebo and other drugs is limited. Trials of longer duration (minimum six months) are needed to investigate the longer-term effects of pimozide compared to atypical neuroleptics. Future trials should use the Yale Global Tic Severity Scale to assess the main outcome measure, and quantify adverse events with the Extrapyramidal Symptoms Rating Scale.

Tremorolytic effects of adenosine A2A antagonists: implications for parkinsonism.

Drug-induced tremulous jaw movements in rats have been used as a model of parkinsonian tremor. Because adenosine A2A antagonists have antiparkinsonian effects, the present experiments were conducted to study the ability of adenosine A2A antagonism to reverse the tremulous jaw movements produced by the antipsychotic drugs pimozide, haloperidol and reserpine. In one group of studies, rats received daily injections of the dopamine antagonist pimozide, and on day 8 they received injections of pimozide plus various doses of the A2A antagonists KW 6002 or MSX-3. KW 6002 and MSX-3 suppressed pimozide-induced tremulous jaw movements, reduced catalepsy, and increased locomotion. MSX-3 also suppressed the jaw movements induced by haloperidol and reserpine. In addition, local injections of MSX-3 into the ventrolateral neostriatum suppressed pimozide-induced tremulous jaw movements. Thus, adenosine A2A antagonism can reverse the tremulous movements induced by antipsychotic drugs, which is consistent with the hypothesis that antagonism of adenosine A2A receptors can result in antiparkinsonian effects. Adenosine A2A antagonists may be useful for their tremorolytic effects, and may help in treating both idiopathic and antipsychotic-induced parkinsonian symptoms.

Delusions of parasitosis.

Delusions of parasitosis is a rare psychiatric disorder in which the patient has a fixed, false belief that he or she is infested by parasites. Even though it is a psychiatric disorder, these patients usually present to a dermatologist because they are convinced that they have a dermatologic problem. Patients with delusions of parasitosis generally reject psychiatric referral. The traditional treatment of choice for delusions of parasitosis is the antipsychotic medication pimozide (Orap, Gate Pharmaceuticals, Philadelphia, PA). The use of pimozide has been limited by its adverse effects, most notably extrapyramidal adverse effects. There is now an emerging role for atypical antipsychotics with a safer adverse effect profile in the treatment of delusions of parasitosis. However, the most challenging aspect of managing these patients may be the challenge of establishing rapport in the face of unshakable delusional ideation.

Chronic Administration of Pimozide Fails to Attenuate Motor and Pathological Deficits in Two Mouse Models of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which presently does not have any efficient therapeutic approach. Pimozide, a Food and Drug Administration (FDA)-approved neuroepileptic drug, has been recently proposed as a promising treatment for ALS patients based on apparent stabilization of right hand muscles after a short-time administration. A new clinical trial started at the end of 2017 to recruit patients with a prolonged drug delivery schedule. Here, our aim was to investigate the effects of chronic administration of pimozide on disease progression and pathological events in two mouse models of ALS. Pimozide was administered every 2 days to transgenic mice bearing the ALS-linked A315T mutation on the human TAR DNA-binding protein 43 (TDP-43) gene and to mice carrying the human superoxide dismutase 1 (SOD1) gene with the ALS-linked G93A mutation. Chronic administration of pimozide exacerbated motor performances in both animal models and reduced survival in SOD1G93A mice. In TDP-43A315T, it decreased the percentage of innervated neuromuscular junctions (NMJs) and increased the accumulation of insoluble TDP-43. In SOD1G93A mice, pimozide had no effects on NMJ innervation or motoneuron loss, but it increased the levels of misfolded SOD1. We conclude that a chronic administration of pimozide did not confer beneficial effects on disease progression in two mouse models of ALS. In light of a new clinical trial on ALS patients with a chronic regime of pimozide, these results with mouse models suggest prudence and careful monitoring of ALS patients subjected to pimozide treatment.

Coadministration of sertraline with cisapride or pimozide: an open-label, nonrandomized examination of pharmacokinetics and corrected QT intervals in healthy adult volunteers.

BACKGROUND: Sertraline hydrochloride is a selective serotonin reuptake inhibitor with demonstrated efficacy and safety for the treatment of the following disorders: major depressive, obsessive-compulsive, panic, premenstrual dysphoric, social anxiety, and posttraumatic stress. Although sertraline is unlikely to cause clinically significant inhibition of cytochrome P450 (CYP) 3A4 substrates, even modest concentration increases for narrow therapeutic index drugs, such as pimozide or cisapride, are potentially important. OBJECTIVE: The goal of this study was to determine whether there is a pharmacokinetic interaction, as shown by plasma concentrations and electrocardiographic evidence of QTc intervals, between sertraline 200 mg QD and cisapride 10 mg QID, and between sertraline 200 mg QD and pimozide (single 2-mg dose). METHODS: Patients in group A were administered cisapride on days 1 and 2 (10 mg QID), day 3 (10 mg/d), days 25 through 29 (10 mg QID), and day 30 (10 mg/d). Sertraline was administered on days 4 through 29 at a starting dose of 50 mg/d, which was titrated upward in 50-mg increments every third day to a maximum of 200 mg/d. Patients in group B were treated with 2 mg of pimozide on days 1 and 39. Sertraline was administered on days 18 through 46 at a starting dose of 50 mg/d, which was titrated upward in 50-mg increments every third day to a maximum of 200 mg/d. RESULTS: There were 9 males and 6 females in group A (sertraline + cisapride) (mean age, 34.4 years for males, 41.7 years for females; mean weight, 78.7 kg for males, 66.6 kg for females; 14 Hispanic, 1 white), and 8 males and 7 females in group B (sertraline + pimozide) (mean age, 26.1 years for males, 33.4 years for females; mean weight, 70.8 kg for males, 61.4 kg for females; 15 Hispanic). Coadministration of sertraline and cisapride resulted in statistically significant reductions of 29% and 36% in cisapride C(max) and AUC from time 0 to 6 hours, respectively, compared with cisapride alone. Coadministration of sertraline and pimozide resulted in statistically significant increases of 35% and 37% in pimozide Cmax and AUC(0-infinity), respectively, compared with pimozide alone. No subject exhibited a prolongation of the QTc interval > or =15% with coadministration of sertraline and cisapride, or sertraline and pimozide. CONCLUSIONS: This study found that coadministration of sertraline with cisapride resulted in decreases in cisapride concentrations, and no significant effects on QTc intervals. Coadministration of sertraline 200 mg/d and a single dose of pimozide 2 mg produced significant increases in pimozide concentrations but no prolongation of the QTc interval > or =15%. This opposite effect for pimozide compared with cisapride, as well as other previously tested CYP3A4 substrates, suggests that there are mechanisms other than CYP3A4 involved in the sertraline-pimozide interaction.

Serum calcium and magnesium levels in schizophrenia. II. Possible relationship to extrapyramidal symptoms.

The relationship between serum calcium and magnesium levels and neuroleptic-induced extrapyramidal symptoms (EPS) was studied in schizophrenic patients. The 16 patients in whom EPS developed had a significantly lower mean drug-free calcium level than the six patients in whom EPS did not develop. In patients in whom EPS developed, drug-free serum calcium and magnesium levels together correlated significantly with the neuroleptic dosage at which EPS first developed; lower calcium and magnesium values predicted EPS at lower dosages. We have previously shown that both serum calcium and magnesium levels were significantly lower during neuroleptic treatment than in the drug-free state. In this study, a similar trend was observed, but the calcium value tended to be, and the magnesium value was significantly lower at the onset of neuroleptic-induced EPS than during the mean of an entire pimozide trial.

Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la Tourette's syndrome.

The results of this controlled study of the treatment of 57 patients with Gilles de la Tourette's syndrome suggested that both haloperidol and pimozide were more effective than placebo, but that haloperidol was slightly more effective than pimozide. Adverse effects occurred more frequently with haloperidol vs placebo than with pimozide vs placebo, but the frequency was not significantly different for haloperidol compared with pimozide. Clinically significant cardiac effects did not occur at a maximum dosage of 0.3 mg/kg or 20 mg/d for pimozide and 10 mg/d for haloperidol. However, the QTc interval was prolonged during pimozide treatment compared with that during haloperidol treatment, although the values for both medications were not in an abnormal range.

Neuroleptic-induced seizures. An in vitro technique for assessing relative risk.

To estimate the relative risk of various neuroleptic medications for patients with epilepsy or likely to have neuroleptic-induced seizures, their action on spike activity in perfused guinea pig hippocampal slices was studied. Within the range of concentrations studied, molindone hydrochloride, butaclamol hydrochloride, pimozide, and fluphenazine dihydrochloride produced the least increase in excitability. There were also differences in the dose-response curves. Chlorpromazine, thioridazine, and pimozide produced an inverted U-shaped curve. For haloperidol and fluphenazine, excitability tended to increase and them plateau. Molindone and butaclamol produced no increase in excitability. Combinations of neuroleptics had synergistic effects, while the anticonvulsant diazepam inhibited neuroleptic-induced excitability. This article discusses the clinical implications of these findings and their effect on theories of which neuroleptics might produce the fewest seizures.

Prolactin monitoring of haloperidol and pimozide treatment in children with Tourette's syndrome.

Neuroleptic therapy of children and adolescents with Tourette's syndrome (GTS) is associated with unpredictable outcome and adverse drug responses (i.e., extrapyramidal symptoms). Assessing the potential outcomes in GTS from a physiologic marker such as plasma prolactin concentration is important in limiting exposure and optimizing therapy. In a double-blind, placebo-controlled, double crossover comparison of pimozide and haloperidol therapy, prolactin, tic severity, and extrapyramidal symptoms were assessed at a 6-week end point. Twenty-six GTS patients (10.5 +/- 2.6 years), experienced clinical response rates of 69% on 3.4 +/- 1.6 mg pimozide and 65% on 3.5 +/- 2.2 mg/day haloperidol. Pimozide responders demonstrate elevated prolactin (26.1 +/- 11.8 ng/mL) versus pimozide nonresponders (10.5 +/- 3.8 ng/mL) (p = .05) and haloperidol treated patients (p = .05). Prolactin may be a marker for tic response to pimozide, and conversely, a potential marker for haloperidol-related incidence of extrapyramidal symptoms during haloperidol therapy.

Treatment of Gilles de la Tourette syndrome with pimozide.

The results of this clinical study of 31 patients with Tourette syndrome suggest that pimozide is more effective and induces fewer side effects than haloperidol in some patients. The clinical advantages of pimozide may be associated with its more specific dopamine-blocking properties and the absence of significant norepinephrine effects. The authors recommend further controlled study of exclusive dopamine antagonists in the treatment of Tourette syndrome.

Tourette syndrome, pimozide, and school phobia: the neuroleptic separation anxiety syndrome.

The development of school phobia has been reported in some patients with Tourette syndrome treated with haloperidol. The author reports on a patient who developed school phobia on each of three trials with pimozide, a neuroleptic chemically similar to haloperidol, and proposes the term "neuroleptic separation anxiety syndrome." The syndrome is clinically indistinguishable from DSM-III criteria for school phobia (separation anxiety disorder). Tricyclic antidepressants may have a therapeutic or prophylactic effect. It is not known whether this neuroleptic side effect occurs in patients other than those with Tourette syndrome.

Relative efficacy of haloperidol and pimozide in children and adolescents with Tourette's disorder.

OBJECTIVE: The authors evaluated the relative efficacy and safety of pimozide and haloperidol in the treatment of Gilles de la Tourette's syndrome in children and adolescents. METHOD: A double-blind, 24-week, placebo-controlled double crossover study of equivalent dose formulations of haloperidol and pimozide was conducted with 22 subjects, aged 7-16 years, with Tourette's disorder who were randomly assigned to first one active drug treatment and then the other. Biweekly assessment and flexible dose titration mimicked clinical practice. The primary outcome variable was total score on the Tourette Syndrome Global Scale. Final outcome was determined after 6 weeks of each treatment (placebo, pimozide, haloperidol), with a 2-week placebo baseline period and intervening 2-week placebo washout periods between treatments. RESULTS: Pimozide proved significantly different from placebo in affecting the primary outcome variable, whereas haloperidol failed to have a significant effect. Haloperidol exhibited a threefold higher frequency of serious side effects and significantly greater extrapyramidal symptoms relative to pimozide. Haloperidol-associated treatment-limiting adverse events were experienced by 41% of the patients. The therapeutic doses of pimozide and haloperidol were equivalent (mean = 3.4 mg/day, SD = 1.6, and mean = 3.5 mg/day, SD = 2.2, respectively). CONCLUSIONS: At equivalent doses, pimozide is superior to haloperidol for controlling symptoms of Tourette's disorder in children and adolescents.